Heterocyclic compounds and their uses

ABSTRACT

Substituted bicyclic heteroaryls and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren&#39;s syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110δ activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer.

This application is a division and claims the benefit of applicationSer. No. 12/079,281, filed Mar. 24, 2008 which claims the benefit ofU.S. Provisional Application No. 60/919,565, filed Mar. 23, 2007, whichare hereby incorporated by reference.

The present invention relates generally to phosphatidylinositol 3-kinase(PI3K) enzymes, and more particularly to selective inhibitors of PI3Kactivity and to methods of using such materials.

BACKGROUND OF THE INVENTION

Cell signaling via 3′-phosphorylated phosphoinositides has beenimplicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity (seeRameh et al., J. Biol Chem, 274:8347-8350 (1999) for a review). Theenzyme responsible for generating these phosphorylated signalingproducts, phosphatidylinositol 3-kinase (PI 3-kinase; PI3K), wasoriginally identified as an activity associated with viral oncoproteinsand growth factor receptor tyrosine kinases that phosphorylatesphosphatidylinositol (PI) and its phosphorylated derivatives at the3′-hydroxyl of the inositol ring (Panayotou et al., Trends Cell Biol2:358-60 (1992)).

The levels of phosphatidylinositol-3,4,5-triphosphate (PIP3), theprimary product of PI 3-kinase activation, increase upon treatment ofcells with a variety of stimuli. This includes signaling throughreceptors for the majority of growth factors and many inflammatorystimuli, hormones, neurotransmitters and antigens, and thus theactivation of PI3Ks represents one, if not the most prevalent, signaltransduction events associated with mammalian cell surface receptoractivation (Cantley, Science 296:1655-1657 (2002); Vanhaesebroeck et al.Annu. Rev. Biochem, 70: 535-602 (2001)). PI 3-kinase activation,therefore, is involved in a wide range of cellular responses includingcell growth, migration, differentiation, and apoptosis (Parker et al.,Current Biology, 5:577-99 (1995); Yao et al., Science, 267:2003-05(1995)). Though the downstream targets of phosphorylated lipidsgenerated following PI 3-kinase activation have not been fullycharacterized, it is known that pleckstrin-homology (PH) domain- andFYVE-finger domain-containing proteins are activated when binding tovarious phosphatidylinositol lipids (Sternmark et al., J Cell Sci,112:4175-83 (1999); Lemmon et al., Trends Cell Biol, 7:237-42 (1997)).Two groups of PH-domain containing PI3K effectors have been studied inthe context of immune cell signaling, members of the tyrosine kinase TECfamily and the serine/threonine kinases of to AGC family. Members of theTec family containing PH domains with apparent selectivity for PtdIns(3,4,5)P₃ include Tec, Btk, Itk and Etk. Binding of PH to PIP₃ iscritical for tyrsosine kinase activity of the Tec family members(Schaeffer and Schwartzberg, Curr. Opin. Immunol. 12: 282-288 (2000))AGC family members that are regulated by PI3K include thephosphoinositide-dependent kinase (PDK1), AKT (also termed PKB) andcertain isoforms of protein kinase C (PKC) and S6 kinase. There arethree isoforms of AKT and activation of AKT is strongly associated withPI3K-dependent proliferation and survival signals. Activation of AKTdepends on phosphorylation by PDK1, which also has a3-phosphoinositide-selective PH domain to recruit it to the membranewhere it interacts with AKT. Other important PDK1 substrates are PKC andS6 kinase (Deane and Fruman, Annu Rev. Immunol. 22_(—)563-598 (2004)).In vitro, some isoforms of protein kinase C (PKC) are directly activatedby PIP3. (Burgering et al., Nature, 376:599-602 (1995)).

Presently, the PI 3-kinase enzyme family has been divided into threeclasses based on their substrate specificities. Class I PI3Ks canphosphorylate phosphatidylinositol (PI),phosphatidylinositol-4-phosphate, andphosphatidyl-inositol-4,5-biphosphate (PIP2) to producephosphatidylinositol-3-phosphate (PIP),phosphatidylinositol-3,4-biphosphate, andphosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3Ksphosphorylate PI and phosphatidyl-inositol-4-phosphate, whereas ClassIII PI3Ks can only phosphorylate PI.

The initial purification and molecular cloning of PI 3-kinase revealedthat it was a heterodimer consisting of p85 and p110 subunits (Otsu etal., Cell, 65:91-104 (1991); Hiles et al., Cell, 70:419-29 (1992)).Since then, four distinct Class I PI3Ks have been identified, designatedPI3K α, β, δ, and γ, each consisting of a distinct 110 kDa catalyticsubunit and a regulatory subunit. More specifically, three of thecatalytic subunits, i.e., p110α, p110β and p110δ, each interact with thesame regulatory subunit, p85; whereas p110γ interacts with a distinctregulatory subunit, p101. As described below, the patterns of expressionof each of these PI3Ks in human cells and tissues are also distinct.Though a wealth of information has been accumulated in recent past onthe cellular functions of PI 3-kinases in general, the roles played bythe individual isoforms are not fully understood.

Cloning of bovine p110α has been described. This protein was identifiedas related to the Saccharomyces cerevisiae protein: Vps34p, a proteininvolved in vacuolar protein processing. The recombinant p110α productwas also shown to associate with p85α, to yield a PI3K activity intransfected COS-1 cells. See Hiles et al., Cell, 70, 419-29 (1992).

The cloning of a second human p110 isoform, designated p110β, isdescribed in Hu et al., Mol Cell Biol, 13:7677-88 (1993). This isoformis said to associate with p85 in cells, and to be ubiquitouslyexpressed, as p110β mRNA has been found in numerous human and mousetissues as well as in human umbilical vein endothelial cells, Jurkathuman leukemic T cells, 293 human embryonic kidney cells, mouse 3T3fibroblasts, HeLa cells, and NBT2 rat bladder carcinoma cells. Such wideexpression suggests that this isoform is broadly important in signalingpathways.

Identification of the p110δ isoform of PI 3-kinase is described inChantry et al., J Biol Chem, 272:19236-41 (1997). It was observed thatthe human p110δ isoform is expressed in a tissue-restricted fashion. Itis expressed at high levels in lymphocytes and lymphoid tissues and hasbeen shown to play a key role in PI 3-kinase-mediated signaling in theimmune system (Al-Alwan etl al. JI 178: 2328-2335 (2007); Okkenhaug etal JI, 177: 5122-5128 (2006); Lee et al. PNAS, 103: 1289-1294 (2006)).P110δ has also been shown to be expressed at lower levels in breastcells, melanocytes and endothelial cells (Vogt et al. Virology, 344:131-138 (2006) and has since been implicated in conferring selectivemigratory properties to breast cancer cells (Sawyer et al. Cancer Res.63:1667-1675 (2003)). Details concerning the P110δ isoform also can befound in U.S. Pat. Nos. 5,858,753; 5,822,910; and 5,985,589. See also,Vanhaesebroeck et al., Proc Nat. Acad Sci USA, 94:4330-5 (1997), andinternational publication WO 97/46688.

In each of the PI3Kα, β, and δ subtypes, the p85 subunit acts tolocalize PI 3-kinase to the plasma membrane by the interaction of itsSH2 domain with phosphorylated tyrosine residues (present in anappropriate sequence context) in target proteins (Rameh et al., Cell,83:821-30 (1995)). Five isoforms of p85 have been identified (p85α,p85β, p55γ, p55α and p50α) encoded by three genes. Alternativetranscripts of Pik3r1 gene encode the p85α, p55α and p50α proteins(Deane and Fruman, Annu Rev. Immunol. 22: 563-598 (2004)). p85α isubiquitously expressed while p85β, is primarily found in the brain andlymphoid tissues (Volinia et al., Oncogene, 7:789-93 (1992)).Association of the p85 subunit to the PI 3-kinase p110α, β, or δcatalytic subunits appears to be required for the catalytic activity andstability of these enzymes. In addition, the binding of Ras proteinsalso upregulates PI 3-kinase activity.

The cloning of p110γ revealed still further complexity within the PI3Kfamily of enzymes (Stoyanov et al., Science, 269:690-93 (1995)). Thep110γ isoform is closely related to p110α and p110β (45-48% identity inthe catalytic domain), but as noted does not make use of p85 as atargeting subunit. Instead, p110γ binds a p101 regulatory subunit thatalso binds to the βγ subunits of heterotrimeric G proteins. The p101regulatory subunit for PI3 Kgamma was originally cloned in swine, andthe human ortholog identified subsequently (Krugmann et al., J BiolChem, 274:17152-8 (1999)). Interaction between the N-terminal region ofp101 with the N-terminal region of p110γ is known to activate PI3Kγthrough Gβγ. Recently, a p101-homologue has been identified, p84 orp87^(PIKAP) (PI3Kγ adapter protein of 87 kDa) that binds p110γ (Voigt etal. JBC, 281: 9977-9986 (2006), Suire et al. Curr. Biol. 15: 566-570(2005)). p87^(PIKAP) is homologous to p101 in areas that bind p110γ andGβγ and also mediates activation of p110γ downstream ofG-protein-coupled receptors. Unlike p101, p87^(PIKAP) is highlyexpressed in the heart and may be crucial to PI3Kγ cardiac function.

A constitutively active PI3K polypeptide is described in internationalpublication WO 96/25488. This publication discloses preparation of achimeric fusion protein in which a 102-residue fragment of p85 known asthe inter-SH2 (iSH2) region is fused through a linker region to theN-terminus of murine p110. The p85 iSH2 domain apparently is able toactivate PI3K activity in a manner comparable to intact p85 (Klippel etal., Mol Cell Biol, 14:2675-85 (1994)).

Thus, PI 3-kinases can be defined by their amino acid identity or bytheir activity. Additional members of this growing gene family includemore distantly related lipid and protein kinases including Vps34 TOR1,and TOR2 of Saccharomyces cerevisiae (and their mammalian homologs suchas FRAP and mTOR), the ataxia telangiectasia gene product (ATR) and thecatalytic subunit of DNA-dependent protein kinase (DNA-PK). Seegenerally, Hunter, Cell, 83:1-4 (1995).

PI 3-kinase is also involved in a number of aspects of leukocyteactivation. A p85-associated PI 3-kinase activity has been shown tophysically associate with the cytoplasmic domain of CD28, which is animportant costimulatory molecule for the activation of T-cells inresponse to antigen (Pages et al., Nature, 369:327-29 (1994); Rudd,Immunity, 4:527-34 (1996)). Activation of T cells through CD28 lowersthe threshold for activation by antigen and increases the magnitude andduration of the proliferative response. These effects are linked toincreases in the transcription of a number of genes includinginterleukin-2 (IL2), an important T cell growth factor (Fraser et al.,Science, 251:313-16 (1991)). Mutation of CD28 such that it can no longerinteract with PI 3-kinase leads to a failure to initiate IL2 production,suggesting a critical role for PI 3-kinase in T cell activation.

Specific inhibitors against individual members of a family of enzymesprovide invaluable tools for deciphering functions of each enzyme. Twocompounds, LY294002 and wortmannin, have been widely used as PI 3-kinaseinhibitors. These compounds, however, are nonspecific PI3K inhibitors,as they do not distinguish among the four members of Class I PI3-kinases. For example, the IC₅₀ values of wortmannin against each ofthe various Class I PI 3-kinases are in the range of 1-10 nM. Similarly,the IC₅₀ values for LY294002 against each of these PI 3-kinases is about1 μM (Fruman et al., Ann Rev Biochem, 67:481-507 (1998)). Hence, theutility of these compounds in studying the roles of individual Class IPI 3-kinases is limited.

Based on studies using wortmannin, there is evidence that PI 3-kinasefunction also is required for some aspects of leukocyte signalingthrough G-protein coupled receptors (Thelen et al., Proc Natl Acad SciUSA, 91:4960-64 (1994)). Moreover, it has been shown that wortmannin andLY294002 block neutrophil migration and superoxide release. However,inasmuch as these compounds do not distinguish among the variousisoforms of PI3K, it remains unclear from these studies which particularPI3K isoform or isoforms are involved in these phenomena and whatfunctions the different Class I PI3K enzymes perform in both normal anddiseased tissues in general. The co-expression of several PI3K isoformsin most tissues has confounded efforts to segregate the activities ofeach enzyme until recently.

The separation of the activities of the various PI3K isozymes has beenadvanced recently with the development of genetically manipulated micethat allowed the study of isoform-specific knock-out and kinase deadknock-in mice and the development of more selective inhibitors for someof the different isoforms. P110α and p110β knockout mice have beengenerated and are both embryonic lethal and little information can beobtained from these mice regarding the expression and function of p110alpha and beta (Bi et al. Mamm. Genome, 13:169-172 (2002); Bi et al. J.Biol. Chem. 274:10963-10968 (1999)). More recently, p110α kinase deadknock in mice were generated with a single point mutation in the DFGmotif of the ATP binding pocket (p110αD^(933A)) that impairs kinaseactivity but preserves mutant p110α kinase expression. In contrast toknock out mice, the knockin approach preserves signaling complexstoichiometry, scaffold functions and mimics small molecule approachesmore realistically than knock out mice. Similar to the p110α KO mice,p110αD^(933A) homozygous mice are embryonic lethal. However,heterozygous mice are viable and fertile but display severely bluntedsignaling via insulin-receptor substrate (IRS) proteins, key mediatorsof insulin, insulin-like growth factor-1 and leptin action. Defectiveresponsiveness to these hormones leads to hyperinsulinaemia, glucoseintolerance, hyperphagia, increase adiposity and reduced overall growthin heterozygotes (Foukas, et al. Nature, 441: 366-370 (2006)). Thesestudies revealed a defined, non-redundant role for p110α as anintermediate in IGF-1, insulin and leptin signaling that is notsubstituted for by other isoforms. We will have to await the descriptionof the p110β kinase-dead knock in mice to further understand thefunction of this isoform (mice have been made but not yet published;Vanhaesebroeck).

P110γ knock out and kinase-dead knock in mice have both been generatedand overall show similar and mild phenotypes with primary defects inmigration of cells of the innate immune system and a defect in thymicdevelopment of T cells (Li et al. Science, 287: 1046-1049 (2000), Sasakiet al. Science, 287: 1040-1046 (2000), Patrucco et al. Cell, 118:375-387 (2004)).

Similar to p110γ, PI3K delta knock out and kinase-dead knock-in micehave been made and are viable with mild and like phenotypes. Thep110δ^(D910A) mutant knock in mice demonstrated an important role fordelta in B cell development and function, with marginal zone B cells andCD5+B1 cells nearly undetectable, and B- and T cell antigen receptorsignaling (Clayton et al. J. Exp. Med. 196:753-763 (2002); Okkenhaug etal. Science, 297: 1031-1034 (2002)). The p110δ^(D910A) mice have beenstudied extensively and have elucidated the diverse role that deltaplays in the immune system. T cell dependent and T cell independentimmune responses are severely attenuated in p110δ^(D910A) and secretionof TH1 (INF-γ) and TH2 cytokine (IL-4, IL-5) are impaired (Okkenhaug etal. J. Immunol. 177: 5122-5128 (2006)). A human patient with a mutationin p110δ has also recently been described. A taiwanese boy with aprimary B cell immunodeficiency and a gamma-hypoglobulinemia ofpreviously unkown aetiology presented with a single base-pairsubstitution, m.3256G to A in codon 1021 in exon 24 of p110δ. Thismutation resulted in a mis-sense amino acid substitution (E to K) atcodon 1021, which is located in the highly conserved catalytic domain ofp110δ protein. The patient has no other identified mutations hisphenotype is consistent with p110δ deficiency in mice as far as studied.(Jou et al. Int. J. Immunogenet. 33: 361-369 (2006)).

Isoform-selective small molecule compounds have been developed withvarying success to all Class I PI3 kinase isoforms (Ito et al. J. Pharm.Exp. Therapeut., 321:1-8 (2007)). Inhibitors to alpha are desirablebecause mutations in p110α have been identified in several solid tumors;for example, an amplification mutation of alpha is associated with 50%of ovarian, cervical, lung and breast cancer and an activation mutationhas been described in more than 50% of bowel and 25% of breast cancers(Hennessy et al. Nature Reviews, 4: 988-1004 (2005)). Yamanouchi hasdeveloped a compound YM-024 that inhibits alpha and delta equi-potentlyand is 8- and 28-fold selective over beta and gamma respectively (Ito etal. J. Pharm. Exp. Therapeut., 321:1-8 (2007)).

P110β is involved in thrombus formation (Jackson et al. Nature Med. 11:507-514 (2005)) and small molecule inhibitors specific for this isoformare thought after for indication involving clotting disorders (TGX-221:0.007 uM on beta; 14-fold selective over delta, and more than 500-foldselective over gamma and alpha) (Ito et al. J. Pharm. Exp. Therapeut.,321:1-8 (2007)).

Selective compounds to p110γ are being developed by several groups asimmunosuppressive agents for autoimmune disease (Rueckle et al. NatureReviews, 5: 903-918 (2006)). Of note, AS 605240 has been shown to beefficacious in a mouse model of rheumatoid arthritis (Camps et al.Nature Medicine, 11: 936-943 (2005)) and to delay onset of disease in amodel of systemic lupus erythematosis (Barber et al. Nature Medicine,11: 933-935 (205)).

Delta-selective inhibitors have also been described recently. The mostselective compounds include the quinazolinone purine inhibitors (PIK39and IC87114). IC87114 inhibits p110δ in the high nanomolar range (tripledigit) and has greater than 100-fold selectivity against p110α, is 52fold selective against p110β but lacks selectivity against p110γ(approx. 8-fold). It shows no activity against any protein kinasestested (Knight et al. Cell, 125: 733-747 (2006)). Using delta-selectivecompounds or genetically manipulated mice (p110δ^(D910A)) it was shownthat in addition to playing a key role in B and T cell activation, deltais also partially involved in neutrophil migration and primed neutrophilrespiratory burst and leads to a partial block of antigen-IgE mediatedmast cell degranulation (Condliffe et al. Blood, 106: 1432-1440 (2005);Ali et al. Nature, 431: 1007-1011 (2002)). Hence p110δ is emerging as animportant mediator of many key inflammatory responses that are alsoknown to participate in aberrant inflammatory conditions, including butnot limited to autoimmune disease and allergy. To support this notion,there is a growing body of p110δ target validation data derived fromstudies using both genetic tools and pharmacologic agents. Thus, usingthe delta-selective compound IC 87114 and the p110δ^(D910A) mice, Ali etal. (Nature, 431: 1007-1011 (2002)) have demonstrated that delta plays acritical role in a murine model of allergic disease. In the absence offunctional delta, passive cutaneous anaphylaxis (PCA) is significantlyreduced and can be attributed to a reduction in allergen-IgE inducedmast cell activation and degranulation. In addition, inhibition of deltawith IC 87114 has been shown to significantly ameliorate inflammationand disease in a murine model of asthma using ovalbumin-induced airwayinflammation (Lee et al. FASEB, 20: 455-465 (2006). These data utilizingcompound were corroborated in p110δ^(D910A) mutant mice using the samemodel of allergic airway inflammation by a different group (Nashed etal. Eur. J. Immunol. 37:416-424 (2007)).

There exists a need for further characterization of PI3Kδ function ininflammatory and auto-immune settings. Furthermore, our understanding ofPI3Kδ requires further elaboration of the structural interactions ofp110δ, both with its regulatory subunit and with other proteins in thecell. There also remains a need for more potent and selective orspecific inhibitors of PI3K delta, in order to avoid potentialtoxicology associated with activity on isozymes p110 alpha (insulinsignaling) and beta (platelet activation). In particular, selective orspecific inhibitors of PI3Kδ are desirable for exploring the role ofthis isozyme further and for development of superior pharmaceuticals tomodulate the activity of the isozyme.

SUMMARY

The present invention comprises a new class of compounds having thegeneral formula

which are useful to inhibit the biological activity of human PI3Kδ.Another aspect of the invention is to provide compounds that inhibitPI3Kδ selectively while having relatively low inhibitory potency againstthe other PI3K isoforms. Another aspect of the invention is to providemethods of characterizing the function of human PI3Kδ. Another aspect ofthe invention is to provide methods of selectively modulating humanPI3Kδ activity, and thereby promoting medical treatment of diseasesmediated by PI3Kδ dysfunction. Other aspects and advantages of theinvention will be readily apparent to the artisan having ordinary skillin the art.

DETAILED DESCRIPTION

One aspect of the invention relates to compounds having the structure:

or any pharmaceutically-acceptable salt thereof, wherein:

X¹ is C(R⁹) or N;

X² is C(R¹⁰) or N;

Z is —CR¹¹═CR¹¹—, —CR¹¹═N—, —N═CR¹¹—, —CR—C(═O)— and —C(═O)—CR¹¹═CR¹¹—;

n is 0, 1, 2 or 3;

R¹ is a direct-bonded or oxygen-linked saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0 or1 R² substituents, and the ring is additionally substituted by 0, 1, 2or 3 substituents independently selected from halo, nitro, cyano,C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl;

R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² isselected from C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,—(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle,—O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)hetero cycle,—NR^(a)(C₁₋₃alkyl)hetero aryl, —NR^(a)(C₁₋₃alkyl)hetero cycle, —(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl all ofwhich are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;

R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁴ is, independently, in each instance, halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl orC₁₋₄haloalkyl;

R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃halo alkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;

R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁷ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁸ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);

R¹¹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ isC₁₋₉alkyl or C₁₋₄alkyl(phenyl) wherein either is substituted by 0, 1, 2,3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I; or R¹¹ is a saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1,2, 3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R^(a) is independently, at each instance, H or R^(b); and

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄ alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

Another aspect of the invention relates to compounds having thestructure:

or any pharmaceutically-acceptable salt thereof, wherein:

X¹ is C(R⁹) or N;

X² is C(R¹⁰) or N;

Z is —CR¹¹═CR¹¹—, —CR¹¹═N—, —N═CR¹¹—, —CR¹¹═CR¹¹—C(═O)— and—C(═O)—CR¹¹═CR¹¹—;

n is 0, 1, 2 or 3;

R¹ is a direct-bonded or oxygen-linked saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0 or1 R² substituents, and the ring is additionally substituted by 0, 1, 2or 3 substituents independently selected from halo, nitro, cyano,C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl;

R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² isselected from C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,—(C₁₋₃alkyl)hetero aryl, —(C₁₋₃alkyl)hetero cycle,—O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)hetero cycle,—NR^(a)(C₁₋₃alkyl)hetero aryl, —NR^(a)(C₁₋₃alkyl)hetero cycle,—(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl allof which are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;

R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁴ is, independently, in each instance, halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl orC₁₋₄haloalkyl;

R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆-spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;

R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁷ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁸ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);

R¹¹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ isC₁₋₉alkyl or C₁₋₄alkyl(phenyl) wherein either is substituted by 0, 1, 2,3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I; or R¹¹ is a saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1,2, 3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R^(a) is independently, at each instance, H or R^(b); and

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

Another aspect of the invention relates to compounds having thestructure:

or any pharmaceutically-acceptable salt thereof, wherein:

X¹ is C(R⁹) or N;

X² is C(R¹⁰) or N;

Z is —CR¹¹═CR¹¹—, —CR¹¹═N—, —N═CR¹¹—, —CR¹¹═CR¹¹—C(═O)— and—C(═O)—CR¹¹═CR¹¹—;

n is 0, 1, 2 or 3;

R¹ is a direct-bonded or oxygen-linked saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0 or1 R² substituents, and the ring is additionally substituted by 0, 1, 2or 3 substituents independently selected from halo, nitro, cyano,C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl;

R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² isselected from C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,—(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle,—O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)hetero cycle,—NR^(a)(C₁₋₃alkyl)hetero aryl, —NR^(a)(C₁₋₃alkyl)hetero cycle,—(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl allof which are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;

R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁴ is, independently, in each instance, halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl orC₁₋₄haloalkyl;

R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;

R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁷ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁸ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);

R¹¹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ isC₁₋₉alkyl or C₁₋₄alkyl(phenyl) wherein either is substituted by 0, 1, 2,3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I; or R¹¹ is a saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1,2, 3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R^(a) is independently, at each instance, H or R^(b); and

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

Another aspect of the invention relates to compounds having thestructure:

or any pharmaceutically-acceptable salt thereof, wherein:

X¹ is C(R⁹) or N;

X² is C(R¹⁰) or N;

Z is —CR¹¹═CR¹¹—, —CR¹¹═N—, —N═CR¹¹—, —CR¹¹—C(═O)— and—C(═O)—CR¹¹═CR¹¹—;

n is 0, 1, 2 or 3;

R¹ is a direct-bonded or oxygen-linked saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0 or1 R² substituents, and the ring is additionally substituted by 0, 1, 2or 3 substituents independently selected from halo, nitro, cyano,C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl;

R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² isselected from C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,—(C₁₋₃alkyl)hetero aryl, —(C₁₋₃alkyl)hetero cycle,—O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)hetero cycle,—NR^(a)(C₁₋₃alkyl)hetero aryl, —NR^(a)(C₁₋₃alkyl)hetero cycle,—(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl allof which are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;

R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁴ is, independently, in each instance, halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl orC₁₋₄haloalkyl;

R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;

R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁷ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁸ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);

R¹¹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ isC₁₋₉alkyl or C₁₋₄alkyl(phenyl) wherein either is substituted by 0, 1, 2,3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I; or R¹¹ is a saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1,2, 3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R^(a) is independently, at each instance, H or R^(b); and

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

Another aspect of the invention relates to compounds having thestructure:

or any pharmaceutically-acceptable salt or hydrate thereof, wherein:

X¹ is C(R⁹) or N;

X² is C(R¹⁰) or N;

Z is —CR¹¹═CR¹¹—, —CR¹¹═N—, —N═CR¹¹—, —CR¹¹═CR¹¹—C(═O)— and—C(═O)—CR¹¹═CR¹¹—;

n is 0, 1, 2 or 3;

R¹ is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms selectedfrom N, O and S, but containing no more than one O or S, wherein theavailable carbon atoms of the ring are substituted by 0, 1 or 2 oxo orthioxo groups, wherein the ring is substituted by 0 or 1 R²substituents, and the ring is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl;

R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² isselected from C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, allof which are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;

R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁴ is, independently, in each instance, halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl orC₁₋₄haloalkyl;

R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;

R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁷ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are substituted by0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br,Cl, F, I and C₁₋₆alkyl;

R⁸ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R⁸ isC₁₋₉alkyl or C₁₋₄alkyl(phenyl) wherein either is substituted by 0, 1, 2,3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I; or R⁸ is a saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1,2, 3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);

R¹¹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ isC₁₋₉alkyl or C₁₋₄alkyl(phenyl) wherein either is substituted by 0, 1, 2,3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I; or R¹¹ is a saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1,2, 3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a);

R^(a) is independently, at each instance, H or R^(b); and

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, X¹ is C(R⁹) and X² is N.

In another embodiment, in conjunction with any of the above or belowembodiments, X¹ is C(R⁹) and X² is)C(R¹⁰.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is phenyl substituted by 0 or 1 R² substituents, and thephenyl is additionally substituted by 0, 1, 2 or 3 substituentsindependently selected from halo, nitro, cyano, C₁₋₄alkyl, OC₁₋₄alkyl,OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is phenyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is phenyl substituted by R², and the phenyl isadditionally substituted by 0, 1, 2 or 3 substituents independentlyselected from halo, nitro, cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl,NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is selected from 2-methylphenyl, 2-chlorophenyl,2-trifluoromethylphenyl, 2-fluorophenyl and 2-methoxyphenyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is a direct-bonded or oxygen-linked saturated,partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic ringcontaining 1, 2, 3 or 4 atoms selected from N, O and S, but containingno more than one O or S, wherein the available carbon atoms of the ringare substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 0 or 1 R² substituents, and the ring is additionallysubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, nitro, cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄-alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is an unsaturated 5- or 6-membered monocyclic ringcontaining 1, 2, 3 or 4 atoms selected from N, O and S, but containingno more than one O or S, wherein the ring is substituted by 0 or 1 R²substituents, and the ring is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is an unsaturated 5- or 6-membered monocyclic ringcontaining 1, 2, 3 or 4 atoms selected from N, O and S, but containingno more than one O or S, wherein the ring is substituted by 0 or 1 R²substituents, and the ring is additionally substituted by 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is an unsaturated 5- or 6-membered monocyclic ringcontaining 1, 2, 3 or 4 atoms selected from N, O and S.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is selected from pyridyl and pyrimidinyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R³ is selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R³ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, R³ is selected from F, Cl, C₁₋₆alkyl, phenyl, benzyl,heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl,heteroaryl and heterocycle are additionally substituted by 0, 1, 2 or 3substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I andC₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁵ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, one R⁵ is S-methyl, the other is H.

In another embodiment, in conjunction with any of the above or belowembodiments, at least one R⁵ is halo, C₁₋₆alkyl, C₁₋₄haloalkyl, orC₁₋₆alkyl substituted by 1, 2 or 3 substituents selected from halo,cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂,NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁶ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁶ is NR^(b)R^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R⁶ is NH₂.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁶ is NHC₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁷ is selected from C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a),NR^(a)R^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle,wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle aresubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁷ is selected from C₁₋₆haloalkyl, Br, Cl, F, I andC₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁷ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁸ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁸ is selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SW, —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R⁸ is C₁₋₉alkyl or C₁₋₄alkyl(phenyl) wherein either issubstituted by 0, 1, 2, 3 or 4 substituents selected from halo,C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁸ is a saturated, partially-saturated or unsaturated 5-,6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atomsselected from N, O and S, but containing no more than one O or S,wherein the available carbon atoms of the ring are substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2, 3or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R⁹ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁹ is selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R⁹ is a saturated, partially-saturated or unsaturated 5-,6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atomsselected from N, O and S, but containing no more than one O or S,wherein the available carbon atoms of the ring are substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2, 3or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R¹⁰ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹⁰ is cyano, nitro, CO₂R^(a), C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a).

Another aspect of the invention relates to a method of treatingPI3K-mediated conditions or disorders.

In certain embodiments, the PI3K-mediated condition or disorder isselected from rheumatoid arthritis, ankylosing spondylitis,osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases,and autoimmune diseases. In other embodiments, the PI3K-mediatedcondition or disorder is selected from cardiovascular diseases,atherosclerosis, hypertension, deep venous thrombosis, stroke,myocardial infarction, unstable angina, thromboembolism, pulmonaryembolism, thrombolytic diseases, acute arterial ischemia, peripheralthrombotic occlusions, and coronary artery disease. In still otherembodiments, the PI3K-mediated condition or disorder is selected fromcancer, colon cancer, glioblastoma, endometrial carcinoma,hepatocellular cancer, lung cancer, melanoma, renal cell carcinoma,thyroid carcinoma, cell lymphoma, lymphoproliferative disorders, smallcell lung cancer, squamous cell lung carcinoma, glioma, breast cancer,prostate cancer, ovarian cancer, cervical cancer, and leukemia. In yetanother embodiment, the PI3K-mediated condition or disorder is selectedfrom type II diabetes. In still other embodiments, the PI3K-mediatedcondition or disorder is selected from respiratory diseases, bronchitis,asthma, and chronic obstructive pulmonary disease. In certainembodiments, the subject is a human.

Another aspect of the invention relates to the treatment of rheumatoidarthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis,psoriasis, inflammatory diseases or autoimmune diseases comprising thestep of administering a compound according to any of the aboveembodiments.

Another aspect of the invention relates to the treatment of rheumatoidarthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis,psoriasis, inflammatory diseases and autoimmune diseases, inflammatorybowel disorders, inflammatory eye disorders, inflammatory or unstablebladder disorders, skin complaints with inflammatory components, chronicinflammatory conditions, autoimmune diseases, systemic lupuserythematosis (SLE), myestenia gravis, rheumatoid arthritis, acutedisseminated encephalomyelitis, idiopathic thrombocytopenic purpura,multiples sclerosis, Sjoegren's syndrome and autoimmune hemolyticanemia, allergic conditions and hypersensitivity, comprising the step ofadministering a compound according to any of the above or belowembodiments.

Another aspect of the invention relates to the treatment of cancers thatare mediated, dependent on or associated with p110δ activity, comprisingthe step of administering a compound according to any of the above orbelow embodiments.

Another aspect of the invention relates to the treatment of cancers areselected from acute myeloid leukaemia, myelo-dysplastic syndrome,myelo-proliferative diseases, chronic myeloid leukaemia, T-cell acutelymphoblastic leukaemia, B-cell acute lymphoblastic leukaemia,non-hodgkins lymphoma, B-cell lymphoma, solid tumors and breast cancer,comprising the step of administering a compound according to any of theabove or below embodiments.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound according to any of the above embodiments and apharmaceutically-acceptable diluent or carrier.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments as a medicament.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments in the manufacture of amedicament for the treatment of rheumatoid arthritis, ankylosingspondylitis, osteoarthritis, psoriatic arthritis, psoriasis,inflammatory diseases, and autoimmune diseases.

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims:

“C_(α-β)alkyl” means an alkyl group comprising a minimum of α and amaximum of β carbon atoms in a branched, cyclical or linear relationshipor any combination of the three, wherein α and β represent integers. Thealkyl groups described in this section may also contain one or twodouble or triple bonds. Examples of C₁₋₆alkyl include, but are notlimited to the following:

“Benzo group”, alone or in combination, means the divalent radicalC₄H₄═, one representation of which is —CH═CH—CH═CH—, that when vicinallyattached to another ring forms a benzene-like ring—for exampletetrahydronaphthylene, indole and the like.The terms “oxo” and “thioxo” represent the groups ═O (as in carbonyl)and ═S (as in thiocarbonyl), respectively.“Halo” or “halogen” means a halogen atoms selected from F, Cl, Br and I.“C_(v-w)haloalkyl” means an alkyl group, as described above, wherein anynumber—at least one—of the hydrogen atoms attached to the alkyl chainare replaced by F, Cl, Br or I.“Heterocycle” means a ring comprising at least one carbon atom and atleast one other atom selected from N, O and S. Examples of heterocyclesthat may be found in the claims include, but are not limited to, thefollowing:

“Available nitrogen atoms” are those nitrogen atoms that are part of aheterocycle and are joined by two single bonds (e.g. piperidine),leaving an external bond available for substitution by, for example, Hor CH₃.“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al., J.Pharm. Sci. 66:1 (1977).“Saturated, partially saturated or unsaturated” includes substituentssaturated with hydrogens, substituents completely unsaturated withhydrogens and substituents partially saturated with hydrogens.“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl,phthaloyl and the like. A mixture of protecting groups can be used toprotect the same amino group, such as a primary amino group can beprotected by both an aralkyl group and an aralkoxycarbonyl group. Aminoprotecting groups can also form a heterocyclic ring with the nitrogen towhich they are attached, for example, 1,2-bis(methylene)benzene,phthalimidyl, succinimidyl, maleimidyl and the like and where theseheterocyclic groups can further include adjoining aryl and cycloalkylrings. In addition, the heterocyclic groups can be mono-, di- ortri-substituted, such as nitrophthalimidyl. Amino groups may also beprotected against undesired reactions, such as oxidation, through theformation of an addition salt, such as hydrochloride, toluenesulfonicacid, trifluoroacetic acid and the like. Many of the amino protectinggroups are also suitable for protecting carboxy, hydroxy and mercaptogroups. For example, aralkyl groups. Alkyl groups are also suitablegroups for protecting hydroxy and mercapto groups, such as tert-butyl.Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-trisilyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′═O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The specification and claims contain listing of species using thelanguage “selected from . . . and . . . ” and “is . . . or . . . ”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups as needed.

EXPERIMENTAL

The following abbreviations are used:

-   aq.—aqueous-   BINAP—2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   cond—concentrated-   DCM dichloromethane-   DMF—N,N-dimethylformamide-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   EtOH—ethyl alcohol-   h—hour(s)-   min—minutes-   MeOH—methyl alcohol-   rt room temperature-   satd—saturated-   THF—tetrahydrofuran

General

Reagents and solvents used below can be obtained from commercialsources. ¹H-NMR spectra were recorded on a Bruker 400 MHz and 500 MHzNMR spectrometer. Significant peaks are tabulated in the order:multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) andnumber of protons. Mass spectrometry results are reported as the ratioof mass over charge, followed by the relative abundance of each ion (inparentheses Electrospray ionization (ESI) mass spectrometry analysis wasconducted on a Agilent 1100 series LC/MSD electrospray massspectrometer. All compounds could be analyzed in the positive ESI modeusing acetonitrile:water with 0.1% formic acid as the delivery solvent.Reverse phase analytical HPLC was carried out using a Agilent 1200series on Agilent Eclipse XDB-C18 5 μm column (4.6×150 mm) as thestationary phase and eluting with acetonitrile:H₂O with 0.1% TFA.Reverse phase Semi-Prep HPLC was carried out using a Agilent 1100 Serieson a Phenomenex Gemini™ 10 μm C18 column (250×21.20 mm) as thestationary phase and eluting with acetonitrile:H₂O with 0.1% TFA.

Procedure A

A mixture of 2-chloro-quinoline-3-carbaldehyde (1 eq), arylboronic acid(1.1 eq), tetrakis(triphenylphosphine)palladium (5 mol %), and sodiumcarbonate (2M aq. Sol., 5.0 eq) in CH₃CN-water (3:1, 0.1 M) was heatedat 100° C. under N₂ for several hours. The mixture was partitionedbetween EtOAc and H₂O, the organic layer was separated, and the aqueouslayer was extracted with EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, concentrated under reduced pressure, and purifiedby column chromatography on silica gel using 0% to 25% gradient of EtOAcin hexane to provide 2-arylquinoline-3-carbaldehydes.

Procedure B

Solid sodium borohydride (1.5 eq) was added to a solution of2-arylquinoline-3-carbaldehyde (1 eq) in THF (0.5M) at 0° C. and themixture was stirred at 0° C. for 2 h. The reaction was quenched byaddition of water. The aqueous layer was extracted with EtOAc (3 times).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel using 50% of EtOAc in hexane to provide(2-arylquinolin-3-yl)methanols.

Procedure C

(2-Arylquinolin-3-yl)methanol (1 eq) in CHCl₃ (0.25M) was treated withSOCl₂ (5 eq) at rt for 2 h. Solvents were removed under reduced pressureand the residue was partitioned between EtOAc and saturated aq. NaHCO₃solution. The organic layer was separated, washed with water and brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude product was purified by column chromatography on a Redi-Sep™column using 0 to 100% gradient of EtOAc in hexane to provide3-(chloromethyl)-2-arylquinolines.

Procedure D

To a solution of 3-(chloromethyl)-2-arylquinoline (1 eq) in DMSO (0.25M) was added NaN₃ (3 eq) at rt and the mixture was stirred for 4 h atrt. The mixture was diluted with water, extracted with EtOAc (2 times)and the combined organic layers were washed with water (2 times), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was dissolved in MeOH and treated with 10% Pd—C (5 wt %) and themixture was then stirred under H₂ balloon over night. The mixture wasfiltered through a celite pad followed by removal of solvents to give(2-arylquinolin-3-yl)methanamines.

Procedure E

To a stirring solution of 3-(chloromethyl)-2-arylquinoline (1 eq) in 16mL of DMF was added NaN₃ (2 eq) at rt. The mixture was stirred at rt for1 h. The mixture was partitioned between EtOAc and H₂O. The organiclayer was dried over MgSO₄, filtered, and concentrated under reducedpressure to provide 3-(azidomethyl)-2-arylquinolines. The crude productwas carried on without purification for the next step. To a stirringsolution of 3-(azidomethyl)-2-arylquinoline in THF—H₂O (4:1, 0.21 M) wasadded dropwise PMe₃ (1.0 M solution in THF, 1.2 eq) at rt and themixture was stirred at rt for 1 h. To the mixture was added EtOAc andthe mixture was extracted with 1N HCl (2 times). The combined extractswere neutralized with solid sodium bicarbonate, and extracted with EtOAc(2 times). The combined organic extracts were dried over MgSO₄,filtered, and concentrated under reduced pressure to give dark syrup.The crude product was purified by column chromatography on a Redi-Sep™column using 0 to 100% gradient of CH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂as eluent to provide (2-arylquinolin-3-yl)methanamines.

Procedure F

A mixture of 2-arylquinoline-3-carbaldehyde (1 eq), DCE (0.2 M), andPMBNH₂ (1.5 eq) was stirred at rt. After 1 h, to the mixture was addedNaBH(OAc)₃ (3 eq) and the mixture was stirred at 50° C. for 2 h. To themixture was added saturated aq. NaHCO₃ and the mixture was stirred for15 min. The organic layer was separated and the aqueous layer wasextracted with CH₂Cl₂ (2 times). The combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography on aRedi-Sep™ column using 0 to 100% gradient of EtOAc in hexane to provideN-(4-methoxybenzyl)(2-arylquinolin-3-yl)methanamines.

Procedures G

A mixture of N-(4-methoxybenzyl)(2-arylquinolin-3-yl)methanamine (1 eq)and ammonium cerium(iv) nitrate (3.5 eq) in CH₃CN—H₂O (2:1, 0.22M) wasstirred at rt for 24 h. To the mixture wad added 0.5M HCl (12 eq) andthe mixture was washed with CH₂Cl₂ (3 times) to remove4-methoxybenzaldehyde produced. The organic fraction was then extractedwith 0.5M HCl (2 times). The combined acidic aqueous layer was basifiedto pH 9.0 with 2N HaOH. The resulting precipitate was collected byfiltration. The crude product was purified by column chromatography on aRedi-Sep™ column using 0 to 100% gradient of CH₂Cl₂:MeOH:NH₄OH (89:9:1)in CH₂Cl₂ as eluent to provide provide(2-arylquinolin-3-yl)methanamines.

Procedure I

A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1 eq) in DMF(0.3M) at 0° C. was treated with NaH (60%, 2.2 eq) for 30 min beforeaddition of a solution of 3-(chloromethyl)-2-arylquinolines (1 eq) inDMF (0.5M). The mixture was stirred at room temperature overnight. Themixture was poured onto ice-water. The resulting precipitate wascollected by suction filtration, washed with water, and air-dried. Thecrude product was purified by column chromatography on a Redi-Sep™column using 0 to 100% gradient of EtOAc in hexane and then 100%isocratic of EtOAc as eluent to provide3-iodo-1-((2-arylquinolin-3-yl)-methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amines.

Procedure J

A mixture of3-iodo-1-((2-arylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(1 eq), boronic acid (2.0 eq), tetrakis(triphenylphosphine)-palladium(10 mol %), and sodium carbonate (2M aq. Sol., 6 eq) in DMF (0.2M) washeated at 100° C. under N₂ for several hours. To the mixture was addedwater. The resulting precipitate was collected by suction filtration,washed with water, and air-dried. The crude product was purified bycolumn chromatography on a Redi-Sep™ column using 0 to 100% gradient ofCH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂ over 14 min as eluent to provide3-substituted-1-((2-phenylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amines.

Procedure K

To a mixture of 2-phenylquinoline-3-carbaldehyde (1.0 eq) in THF (0.28M)at 0° C. was added dropwise a solution of a Grignard reagent (3 M, 2 eq)and the reaction was stirred overnight before being quenched with NH₄Clsaturated solution. The mixture was extracted with EtOAc (2×10 mL) andthe combined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (eluent: EtOAc/hexane, 1/1) to provide1-(2-phenylquinolin-3-yl)alcohols.

Procedure L Preparation ofN-((5-Chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-9H-purin-6-amine3-Chlorobenzene-1,2-diamine

To a solution of 3-chloro-2-nitroaniline (10.00 g, 57.95 mmol), 3 N aq.HCl (96.58 mL, 289.7 mmol), and ethyl alcohol (148.6 mL, 57.95 mmol) wasadded Tin(II) chloride dihydrate (65.96 g, 289.7 mmol) and the mixturewas heated under reflux with stirring. After 3 h, the mixture was cooledto room temperature and concentrated under reduced pressure to give abrown syrup. The mixture was cautiously treated with an excess of 10 MKOH (115.9 mL, 1159 mmol, 20 eqv.). The mixture was diluted with EtOAc(200 mL), filtered through Celite™ pad, and washed the pad well withEtOAc (100 mL×2). The filtrate was extracted with EtOAc (100 mL×2). Thecombined organic layers were washed with water (100 mL×1), dried overMgSO₄, filtered, and concentrated under reduced pressure to give3-chlorobenzene-1,2-diamine as a red oil: ¹H NMR (400 MHz, DMSO-d₆) δppm 6.43-6.53 (2H, m), 6.38 (1H, t, J=7.8 Hz), 4.80 (2H, s), 4.60 (2H,s); LC-MS (ESI) m/z 142.9 [M+H]⁺. The crude product was carried on crudewithout purification for the next step.

1-(2-Chlorophenyl)propane-1,2-dione

To a solution of 2-chlorophenylacetone (10.800 g, 64.049 mmol) in 279 mLof CH₂Cl₂, pyridinium chlorochromate (41.418 g, 192.15 mmol), andpyidine (16 mL) in three portions were added over 2.5 hours and themixture was refluxed under vigorous stirring. After 22 h, he mixture wasremoved from heat. The mixture was concentrated in vacuo to give a darkred syrup. The crude mixture was purified by column chromatography on a120 g of Redi-Sep™ column using 0-10% gradient of EtOAc in hexane over28 min as eluent to give 1-(2-chlorophenyl)propane-1,2-dione as yellowliquid: ¹H NMR (400 MHz, choroform-d) δ ppm 7.66 (1H, dd, J=7.6, 1.8Hz), 7.49-7.54 (1H, m), 7.38-7.45 (2H, m), 2.58 (3H, s); LC-MS: m/z182.9 [M+H]⁺.

3-Bromo-1-(2-chlorophenyl)propane-1,2-dione

A mixture of 1-(2-chlorophenyl)propane-1,2-dione (4.2379 g, 23.208mmol), bromine (1.1891 mL, 23.208 mmol), and glacial acetic acid(0.67005 mL, 11.604 mmol) in chloroform (58.020 mL, 23.208 mmol) washeated at 60° C. After 17 h of stirring at 60° C., the mixture wasremoved from heat and concentrated under reduced pressure to give3-bromo-1-(2-chlorophenyl)propane-1,2-dione as an orange liquid: LC-MS:a peak of m/z 261.0 [M+H(⁷⁹Br)]⁺ and 262.9 [M+H (⁸¹Br)—]⁺. The orangeliquid was carried on crude without purification for the next step.

Example 19-((2-(2-Chlorophenyl)-8-methylquinolin-3-yl)methyl)-9H-purin-6-amine

9-((2-(2-Chlorophenyl)-8-methylquinolin-3-yl)methyl)-9H-purin-6-amine. Amixture of 3-(bromomethyl)-2-(2-chlorophenyl)-8-methylquinoline (66 mg,0.19 mmol), {prepared in a similar way as3-(bromomethyl)-8-methyl-2-o-tolyl-quinoline, example 9} adenine (39 mg,0.29 mmol), and cesium carbonate (124 mg, 0.38 mmol) in DMF (0.7 mL) wasstirred at rt for 2 h. The crude mixture was evaporated onto silica geland purified by flash chromatography (Biotage Si 25+M) eluting withMeOH/CH₂Cl₂ (5% to 10%). The resulting white solid was further purifiedby HPLC (Berger SFC) eluting with i-PrOH/CO₂/DEA to provide a whitesolid [PI3Kδ IC₅₀=2130 nM]. MS (ESI+) m/z=401.1 (M+1).

Example 2 Preparation of4-Amino-8-((2-(2-chlorophenyl)-8-methyl-quinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one

To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.1 g, 0.616mmol), Cs₂CO₃ (0.3013 g, 0.925 mmol, 1.5 eq), and KI (0.0102 g, 0.0616mmol, 0.1 eq) in DMF (2 mL) was added3-(chloromethyl)-2-(2-chlorophenyl)-8-methyl-quinoline (0.2049 g, 0.678mmol, 1.1 eq) and the mixture was stirred at 140° C. for 2.5 h. Themixture was concentrated under reduced pressure. The crude product waspurified by column chromatography on a 40 g of Redi-Sep™ column using 0to 100% gradient of EtOAc in hexane over 14 min and then 100% isocraticof EtOAc for 10 min as eluent to provide4-amino-8-((2-(2-chlorophenyl)-8-methyl-quinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-oneas white solid. The white solid was triturated with EtOAc-Hexane (1:1)and filtered to provide4-amino-8-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one[PI3Kδ IC₅₀=58 nM] as white solid. ¹H NMR (DMSO-d₆) δ ppm 9.53 (1H, d,J=4.7 Hz), 8.13 (1H, s), 8.04-8.11 (2H, m), 7.84 (1H, d, J=7.8 Hz), 7.78(1H, d, J=7.8 Hz), 7.64 (1H, d, J=7.0 Hz), 7.38-7.59 (5H, m), 6.12 (1H,d, J=7.8 Hz), 5.40 (2H, d, J=6.3 Hz), 2.64 (3H, s). Mass Spectrum (ESI)m/e=428.0 (M+1).

Example 33-Iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine3-(Chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline

Prepared according to Procedure B using8-methyl-2-(2-(trifluoromethyl)phenyl)-quinoline-3-carbaldehyde (1.6541g, 5.25 mmol) and solid NaBH₄ (0.2977 g, 7.87 mmol, 1.5 eq) in THF (26mL) followed by Procedure C using the crude(8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanol and SOCl₂(1.9 mL, 26.23 mmol, 5 eq) in CHCl₃ (26 mL). After purification,3-(chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline wasobtained as as yellow syrup. ¹H NMR (DMSO-d₆) δ ppm 8.60 (1H, s), 7.92(2H, dd, J=11.5, 8.0 Hz), 7.72-7.85 (2H, m), 7.67 (2H, dd, J=14.3, 7.2Hz), 7.54-7.62 (1H, m), 4.71 (2H, dd, J=89.8, 11.9 Hz), 2.62 (3H, s).Mass Spectrum (ESI) m/e=336.1 (M+1).

3-Iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Prepared according to Procedure I using3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.41 g, 1.6 mmol, 1 eq) inDMF (5 mL), NaH (60%, 0.138 g, 3.5 mmol, 2.2 eq), and3-(chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline (0.58g, 1.7 mmol, 1 eq) in DMF (3 mL). After purification,3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminewas obtained as white solid. ¹H NMR (DMSO-d₆) δ ppm 8.27 (1H, s), 7.99(1H, s), 7.88 (1H, d, J=7.8 Hz), 7.73-7.79 (1H, m), 7.65 (1H, d, J=6.7Hz), 7.51-7.61 (3H, m), 7.28-7.35 (1H, m), 5.41-5.54 (2H, m), 2.60 (3H,s). Mass Spectrum (ESI) m/e=561.0 (M+1).

Example 43-Iodo-1-((8-methyl-2-o-tolylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Prepared according to Procedure I. A solution of3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 1.5 mmol) in DMF (5mL) at 0° C. was treated with NaH (60%, 67.4 mg, 1.1 eq) for 30 minbefore addition of a solution of3-(chloro-methyl)-8-methyl-2-o-tolylquinoline (435 mg, 1 eq) in DMF (2mL). The mixture was stirred at room temperature over night. Thereaction mixture was partitioned between DCM (50 mL) and water (50 mL).The insoluble was filtered and washed with DCM and water. The organiclayer from the filtrate was separated, dried over Na₂SO₄, concentratedand purified by column chromatography on silica gel (eluent: DCM/MeOH,25/1) to provide a white solid [PI3Kδ IC₅₀=6 nM]. ¹H-NMR (DMSO-d⁶) δ7.96 (s, 1H), 7.85 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.44 (d, J=7.0 Hz,1H), 7.31 (t, J=7.1 Hz, 1H), 6.94-6.99 (m, 4H), 5.26 (s, 2H), 2.45 (s,3H), 1.79 (s, 3H). Mass Spectrum (ESI) m/e=507 (M+1).

Example 5 Preparation of1-((8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)-methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Prepared according to Procedure I using8-chloro-3-(chloromethyl)-2-(2-chloro-phenyl)quinoline (0.235 g, 0.73mmol), NaH (0.047 g 60% in oil, 1.17 mmol, 1.6 eq) and3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.209 g, 0.8 mmol, 1.1 eq)in DMF.1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-aminewas obtained after purification as a white solid [PI3Kδ IC₅₀=14 nM]. 1HNMR (400 MHz, DMSO-d₆) δ ppm 8.42 (1H, s), 8.09 (1H, dd, J=8.6, 1.2 Hz),7.98-8.05 (2H, m), 7.66 (1H, t), 7.48 (1H, dd, J=8.2, 0.8 Hz), 7.36 (1H,dt, J=7.8, 1.6 Hz), 7.25 (1H, dt, J=7.4, 1.2 Hz), 7.13 (1H, dd, J=7.4,1.6 Hz), 5.53 (2H, s) Mass Spectrum (ESI) m/e=547.0 and 549.0 (M+1)

Example 6 Preparation of1-((8-Chloro-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine8-Chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde

Prepared according to Procedure A using 2,8-dichloroquinoline3-carbaldehyde (1.0 g, 4.42 mmol), 2-trifluoromethylphenyl boronic acid(0.924 g, 4.87 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium(0.256 g, 0.221 mmol, 0.05 eq), and sodium carbonate (2.34 g, 22.1 mmol,5 eq) in acetonitrile (30 mL) and water (10 mL). After purification,2-(2-trifluoromethylphenyl)-8-chloroquinoline-3-carb-aldehyde wasobtained as a yellow solid. 1H NMR (500 MHz, DMSO-d₆) δ ppm 9.95 (1H,s), 9.19 (1H, s), 8.33 (1H, dd, J=8.5, 1.2 Hz), 8.20 (1H, dd, J=7.3, 1.2Hz), 7.95 (1H, d, J=7.3 Hz), 7.74-7.87 (2H, m), 7.63 (1H, d, J=7.3 Hz)Mass Spectrum (ESI) m/e=336.1 and 338.0 (M+1)

(8-Chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanol

Prepared according to Procedure B using8-chloro-2-(2-trifluoromethylphenyl) quinoline-3-carbaldehyde (1.10 g,3.28 mmol) and sodium borohydride (0.186 g, 4.91 mmol, 1.5 eq) in THF(15 mL). (8-chloro-2-(2-trifluoromethylphenyl)-quinolin-3-yl)methanolwas obtained as a white solid. 1H NMR (500 MHz, DMSO-d₆) δ ppm 8.57 (1H,s), 8.10 (1H, dd, J=7.9, 1.2 Hz), 7.94 (2H, t, J=6.4 Hz), 7.82 (1H, t,J=7.6 Hz), 7.76 (1H, t, J=7.6 Hz), 7.50-7.68 (4H, m), 5.54 (1H, t, J=5.2Hz), 4.45 (1H, br d), 4.28 (1H, br d) Mass Spectrum (ESI) m/e=338.0 and340.0 (M+1)

8-Chloro-3-(chloromethyl)-2-(2-(trifluoromethyl)phenyl)quinoline

Prepared according to Procedure C using(8-chloro-2-(2-trifluoromethylphenyl)-quinolin-3-yl)methanol (1.10 g,3.26 mmol) and SOCl₂ (1.19 mL, 16.3 mmol, 5 eq) in dichloromethane (5mL). 8-chloro-3-(chloromethyl)-2-(2-trifluoromethyl-phenyl)quinoline wasobtained as a yellow syrup. 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.75 (1H,s), 8.10 (1H, d, J=8.2 Hz), 8.02 (1H, d, J=6.3 Hz), 7.95 (1 H, d, J=7.4Hz), 7.72-7.87 (2H, m), 7.58-7.71 (2H, m), 4.71 (2H, dd, J=82.2, 12.1Hz) Mass Spectrum (ESI) m/e=356.0 and 358.0 (M+1).

1-((8-Chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Prepared according to Procedure I using8-chloro-3-(chloromethyl)-2-(2-trifluoro-methylphenyl)quinoline (0.356g, 1.0 mmol), NaH (0.044 g 60% in oil, 1.1 mmol, 1.1 eq) and3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.287 g, 1.1 mmol, 1.1 eq)in 5 mL DMF.1-((8-Chloro-2-(2-trifluoromethylphenyl)quinolin-3-yl)-methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine[PI3Kδ IC₅₀=7 nM] was obtained after purification as a white solid. 1HNMR (400 MHz, DMSO-d₆) δ ppm 8.40 (1H, s), 8.08 (1H, d, J=8.2 Hz),7.96-8.03 (2H, m), 7.74-7.84 (1H, m), 7.56-7.70 (3H, m), 7.26-7.37 (1H,m), 5.47 (2H, s) Mass Spectrum (ESI) m/e=580.9 and 583.0 (M+1)

Example 7 Preparation of1-((2-(2-Fluorophenyl)-8-methylquinolin-3-yl)-methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine2-(2-Fluorophenyl)-8-methylquinoline-3-carbaldehyde

Prepared according to Procedure A using 2-chloro-8-methylquinoline3-carbaldehyde (1.0 g, 4.86 mmol), 2-fluorophenyl boronic acid (0.749 g,5.35 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.281 g, 0.24mmol, 0.05 eq), and sodium carbonate (2.58 g, 24 mmol, 5 eq) inacetonitrile (36 mL) and water (12 mL). After purification,2-(2-fluorophenyl)-8-methylquinoline-3-carbaldehyde was obtained as ayellow solid. 1H NMR (400 MHz, DMSO-d₆) δ ppm 10.03 (1H, d, J=3.5 Hz),8.99 (1H, s), 8.12 (1H, d, J=7.8 Hz), 7.85 (1H, d, J=7.0 Hz), 7.76 (1H,td, J=7.5, 1.8 Hz), 7.58-7.70 (2H, m), 7.45 (2H, td, J=7.5, 1.0 Hz),7.38 (2H, td, J=9.4, 1.2 Hz), 2.75 (3H, s) Mass Spectrum (ESI) m/e=266.0(M+1)

(2-(2-Fluorophenyl)-8-methylquinolin-3-yl)methanol

Prepared according to Procedure B using2-(2-fluorophenyl)-8-methylquinoline-3-carbaldehyde (0.725 g, 2.73mmol), and sodium borohydride (0.155 g, 4.1 mmol, 1.5 eq) in THF (15mL). (2-(2-fluorophenyl)-8-methylquinolin-3-yl)methanol was obtained asa yellow solid. 1H NMR (500 MHz, DMSO-d₆) δ ppm 8.46 (1H, s), 7.90 (1H,d, J=7.9 Hz), 7.63 (1H, d, J=6.7 Hz), 7.50-7.60 (3H, m), 7.38 (1H, d,J=7.9 Hz), 7.35-7.37 (1H, m), 5.42 (1H, t, J=5.5 Hz), 4.50 (2H, d, J=5.5Hz), 2.69 (3H, s) Mass Spectrum (ESI) m/e=268.1 (M+1)

3-(Chloromethyl)-2-(2-fluorophenyl)-8-methylquinoline

Prepared according to Procedure C using(2-(2-fluorophenyl)-8-methylquinolin-3-yl)methanol (0.700 g, 2.62 mmol)in SOCl₂ (2 mL, 27.4 mmol, 10.5 eq).3-(chloromethyl)-2-(2-fluorophenyl)-8-methyl-quinoline (0.665 g, 89%)was obtained after purification as a brown foam. 1H NMR (500 MHz,DMSO-d₆) δ ppm 8.61 (1H, s), 7.92 (1H, d, J=7.9 Hz), 7.71 (1H, d, J=6.7Hz), 7.53-7.66 (3H, m), 7.40 (2H, t, J=7.9 Hz), 4.81 (2H, s), 2.69 (3H,s) Mass Spectrum (ESI) m/e=286.1 and 288.1 (M+1)

1-((2-(2-Fluorophenyl)-8-methylquinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Prepared according to Procedure I using(2-(2-fluorophenyl)-8-methylquinolin-3-yl)methanamine (0.200 g, 0.7mmol), NaH (0.031 g, 60% in oil, 0.77 mmol, 1.1 eq) and3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.201 g, 0.77 mmol, 1.1 eq)in DMF.1-((2-(2-fluorophenyl)-8-methylquinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine[PI3Kδ IC₅₀=4 nM] was obtained after purification as a white solid. 1HNMR (500 MHz, DMSO-d₆) δ ppm 8.09 (1H, s), 8.00 (1H, s), 7.96 (1H, s),7.80 (1H, d, J=7.9 Hz), 7.63 (1H, d, J=7.3 Hz), 7.46-7.53 (1H, m), 7.30(1H, dt), 7.08 (1H, dd, J=7.6, 1.5 Hz), 7.02 (1H, d, J=7.9 Hz), 6.91(1H, t, J=7.3 Hz), 5.46-5.54 (2H, m), 2.90 (3H, s) Mass Spectrum (ESI)m/e=511.0 (M+1)

Example 83-(4-Amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol

Prepared according to Procedure J using3-iodo-1-((8-methyl-2-(2-(trifluoro-methyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.1 g, 0.1785 mmol, 1 eq), 3-hydroxyphenylboronic acid (0.0492 g, 0.357mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium (0.0206 g, 0.0178mmol, 10 mol %), and sodium carbonate (2M aq. sol, 0.535 mL, 1.07 mmol.,6 eq) in DMF (1 mL). After purification,3-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenolwas obtained as light gray solid. The gray solid was suspended in CH₂Cl₂and filtered to provide3-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol[PI3Kδ IC₅₀=8 nM] as off-white solid. ¹H NMR (DMSO-d₆) δ ppm 9.65 (1H,s), 8.28 (1H, s), 8.04 (1H, s), 7.87 (1H, d, J=7.8 Hz), 7.74-7.80 (1H,m), 7.64 (1H, d, J=7.0 Hz), 7.56-7.61 (2H, m), 7.50-7.56 (1H, m),7.34-7.38 (1H, m), 7.30 (1H, t, J=7.8 Hz), 6.94-7.02 (2H, m), 6.80-6.87(1H, m), 5.53 (2H, s), 2.60 (3H, s). Mass Spectrum (ESI) m/e=527.2(M+1).

Example 93-(4-Amino-1-((8-methyl-2-o-tolylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol

Prepared according to Procedure J. A mixture of3-iodo-1-((8-methyl-2-O-tolylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(51 mg, 0.1 mmol), 3-hydroxyphenylboronic acid (15.2 mg, 1.1 eq), sodiumcarbonate (55 mg, 5 eq), tetrakis(triphenylphosphine)palladium (6 mg, 5%mmol) in DMF (1 mL) and water (0.3 mL) was heated to 100° C. under N₂for 4 h. The reaction mixture was cooled to room temperature, filteredand purified by reverse HPLC (MeCN/H₂O/0.1% TFA) on C18 to give a whitesolid [PI3Kδ IC₅₀=7 nM]. ¹H-NMR (DMSO-d⁶) δ 8.37 (s, 1H), 8.35 (s, 1H),7.86 (d, J=8.2 Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H),7.31 (t, J=7.8 Hz, 1H), 7.14-7.17 (m, 4H), 6.87-6.97 (m, 4H), 5.63 (s,br, 2H), 2.63 (s, 3H), 1.91 (s, 3H). Mass Spectrum (ESI) m/e=473 (M+1).

Example 10 Preparation of3-(4-Amino-1-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol

Prepared according to Procedure J using1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.100 g, 0.18 mmol), 3-(hydroxyphenyl)boronic acid (0.050 g, 0.37 mmol,2 eq), tetrakis(triphenyl-phosphine)palladium (0.021 g, 0.018 mmol, 0.1eq) and 2M aq sodium carbonate (0.54 mL, 1.08 mmol, 6 eq) in DMF (1 mL).3-(4-Amino-1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol[PI3Kδ IC₅₀=14 nM] was obtained after purification as a white solid. 1HNMR (400 MHz, DMSO-d₆) δ ppm 9.52 (1H, s), 8.31 (1H, s), 7.91-8.00 (2H,m), 7.86 (1H, dd, J=7.4, 1.2 Hz), 7.52 (1H, t, J=7.8 Hz), 7.35 (1H, d,J=8.2 Hz), 7.07-7.28 (3H, m), 6.97-7.05 (1H, m), 6.78-6.93 (2H, m), 6.70(1H, dd, J=8.2, 1.6 Hz), 5.36-5.57 (2H, m) Mass Spectrum (ESI) m/e=513.1and 515.0 (M+1).

Example 111-((2-(2-Chlorophenyl)-8-methylquinolin-3-yl)methyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a stirred solution of 3-methyl-1H-pyrazole[3,4-d]pyrimidin-4-amine¹(59 mg, 0.397 mmol) in DMF (1.65 mL) at room temperature was addedsodium hydride (26.5 mg, 0.662 mmol) at once. After 25 minutes,3-(chloromethyl)-2-(2-chloro-phenyl)-8-methylquinoline (100 mg, 0.331mmol) was added, the mixture was stirred for several days. The reactionmixture was poured into H₂O and extracted with Et₂O washed with brineand dried over MgSO₄ [PI3Kδ IC₅₀=137 nM]. Chromatography:Gradient89:9:1/DCM. ¹H NMR (DMSO-d₆) δ ppm 8.07 (1H, s), 7.96 (1H, s), 7.82 (1H,d, J=7.8 Hz), 7.64 (1H, d, J=7.0 Hz), 7.48-7.55 (2H, d, m), 7.34-7.40(1H, m), 7.24-7.30 (1H, m), 7.16-7.21 (1H, m), 5.40 (2H, s), 2.64 (3H,s), 2.44 (3H, s), 7.36-7.40 (2H, m), 7.30-7.36 (1H, m), 6.12 (1H, d,J=5.5 Hz), 4.41 (2H, d, J=4.7 Hz), 2.67 (3H, s), 2.14 (3H, s). MassSpectrum (ESI) m/e=415.1 (M+1).

Example 121-((8-Methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Prepared according to Procedure J using3-iodo-1-((8-methyl-2-(2-(tri-fluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.1000 g, 0.178 mmol, 1 eq), pyrazole-4-boronic acid pinacol ester(0.0693 g, 0.357 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium(0)(0.0206 g, 0.0178 mmol, 10 mol %), and sodium carbonate (2M aq. sol,0.535 mL, 1.07 mmol., 6 eq) in DMF (1 mL). After purification,1-((8-methyl-2-(2-(trifluoromethyl)-phenyl)quinolin-3-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminewas obtained as white solid. The white solid was suspended in CH₂Cl₂ andfiltered to give the desired product as white solid [PI3Kδ IC₅₀=8 nM].¹H NMR (DMSO-d₆) δ ppm 13.17 (1H, s), 8.22 (1H, s), 7.97-8.08 (2H, m),7.71-7.90 (3H, m), 7.56-7.66 (3H, m), 7.52 (1H, dd, J=7.8, 7.0 Hz),7.35-7.44 (1H, m), 6.82 (2H, br. s.), 5.42-5.55 (2H, m), 2.60 (3H, s).Mass Spectrum (ESI) m/e=501.1 (M+1).

Example 133-Cyclopropyl-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.1000 g, 0.18 mmol), cyclopropylboronic acid (0.020 g, 0.23 mmol, 1.3eq), tripotassium phosphate (0.13 g, 0.62 mmol, 3.5 eq), andtricyclohexylphosphine (0.0050 g, 0.018 mmol, 0.1 eq) in toluene (2 mL)and water (0.1 mL) under nitrogen atmosphere was added palladium acetate(0.0020 g, 0.0089 mmol, 5 mol %). The mixture was heated at 90° C. for62 h. To the mixture was added water (30 mL). The mixture was extractedwith EtOAc (30 mL×2). The combined organic layers were washed with brine(50 mL×1), dried over MgSO₄, filtered, and concentrated under reducedpressure to provide a yellow syrup. The yellow syrup was purified bycolumn chromatography on a 40 g of Redi-Sep™ column using 50 to 100%gradient of EtOAc in hexane over 9 min, 100% isocratic of EtOAc for 8min, and then 0 to 100% gradient of CH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂over 14 min as eluent to provide3-cyclopropyl-1-((8-methyl-2-(2-(trifluoromethyl)-phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine[PI3Kδ IC₅₀=149 nM] as yellow solid. ¹H NMR (DMSO-d₆) δ ppm 8.08 (1H,s), 7.98 (1H, s), 7.77-7.85 (2H, m), 7.59-7.68 (3H, m), 7.51 (1H, dd,J=7.8, 7.0 Hz), 7.37-7.44 (1H, m), 5.34 (2H, s), 2.59 (3H, s), 2.31-2.42(1H, m), 0.84-0.93 (2H, m), 0.70-0.78 (2H, m). Mass Spectrum (ESI)m/e=475.1 (M+1).

Example 144-(4-Amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methylbut-3-yn-2-ol

A suspension of3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.0569 g, 0.102 mmol) and copper(i) iodide (0.00387 g, 0.0203 mmol, 0.2eq) in DMF (2 mL) was treated with 2-methyl-3-butyn-2-ol (0.0984 mL,1.02 mmol, 10 eq), triethylamine (0.0282 mL, 0.203 mmol, 2 eq) andtetrakis(triphenylphosphine)palladium(0) (0.0117 g, 0.0102 mmol, 10 mol%) under Ar. The mixture was stirred under Ar at rt for 45 min. Themixture was concentrated under reduced pressure. The residue waspurified by column chromatography on a 40 g of Redi-Sep™ column using 0to 100% gradient of CH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂ over 14 min aseluent to provide4-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methylbut-3-yn-2-ol[PI3Kδ IC₅₀=116 nM] as a tan solid. ¹H NMR (DMSO-d₆) δ ppm 8.21 (1H, s),8.02 (1H, s), 7.87 (1H, d, J=7.8 Hz), 7.77-7.82 (1H, m), 7.65 (1H, d,J=6.7 Hz), 7.57-7.62 (2H, m), 7.51-7.57 (1H, m), 7.26-7.32 (1H, m), 5.76(1H, s), 5.44 (2H, s), 2.60 (3H, s), 1.46 (6H, s). Mass Spectrum (ESI)m/e=517.2 (M+1).

Examples 15 and 161-((3-(2-Chlorophenyl)-8-methylquinoxalin-2-yl)-methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((3-(2-Chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.8909 g,3.41 mmol, 1 eq) 10 mL of DMF (10 mL) was added sodium hydride, 60%dispersion in mineral oil (0.2730 g, 6.83 mmol, 2 eq) at 0° C. and themixture was stirred at rt. After 10 min at rt, to the mixture was addeda solution of 3-(bromomethyl)-2-(2-chlorophenyl)-5-methylquinoxaline and2-(bromomethyl)-3-(2-chlorophenyl)-5-methylquinoxaline (preparedaccording to procedures shown in Example 15 and 16, 1.2458 g, 3.58 mmol)in DMF (5 mL) and the mixture was stirred at rt for 1 h. The mixture waspoured into ice-water (100 mL). The resulting precipitate was collectedby filtration to provide yellow solid. The yellow solid was purified bycolumn chromatography on a 80 g of Redi-Sep™ column using 9% isocraticof CH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂ for 20 min and then 9% to 100%gradient of CH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂ over 20 min as eluentto provide a mixture of1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineas yellow foamy solid. The yellow foamy solid (0.1 g) was dissolved in 5mL of MeOH—CH₃CN (0.1% of TFA) and purified by semi-prep-HPLC on C18column using 30-90% gradient of CH₃CN (0.1% of TFA) in water (0.1% ofTFA) over 40 min as eluent to provide1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine[PI3Kδ IC₅₀=38 nM] as white solid and1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine[PI3Kδ IC₅₀=21 nM] as a TFA salt. ¹H NMR (DMSO-d₆) δ ppm 8.05 (1H, s),7.93 (1H, dd, J=8.0, 1.0 Hz), 7.77-7.82 (1H, m), 7.72-7.77 (1H, m), 7.48(1H, d, J=7.8 Hz), 7.33-7.39 (1H, m), 7.27-7.32 (2H, m), 5.74 (2H, s),2.54 (3H, s); Mass Spectrum (ESI) m/e=528.0 (M+1); HPLC: a peak at 7.834min. ¹H NMR (DMSO-d₆) δ ppm 8.02 (1H, s), 7.93 (1H, d, J=8.5 Hz), 7.82(1H, t, J=7.6 Hz), 7.75-7.79 (1H, m), 7.43 (1H, d, J=7.9 Hz), 7.28-7.34(1H, m), 7.19-7.26 (2H, m), 5.75 (2H, br. s.), 2.68 (3H, s); MassSpectrum (ESI) m/e=528.0 (M+1); HPLC: a peak at 8.039 min.

Example 17 and 181-((3-(2-Chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((3-(2-Chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Prepared according to Procedure J using a mixture of1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.2737 g, 0.52 mmol, 1 eq), 4-pyrazoleboronic acid pinacol ester (0.20g, 1.0 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium(0) (0.060 g,0.052 mmol, 10 mol %), and sodium carbonate (2M aq. sol, 1.6 mL, 3.1mmol, 6 eq) in DMF (3.1 mL). After purification, a mixture of1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminewas obtained as tan solid. The tan solid (0.1566 g) was dissolved inDMSO (8 mL) and purified by semi-prep-HPLC on C18 column using 20-70%gradient of CH₃CN (0.1% of TFA) in water (0.1% of TFA) over 40 min aseluent to provide1((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine[PI3Kδ IC₅₀=18 nM] as white solid as a TFA salt and1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine[PI3Kδ IC₅₀=30 nM] as white solid as a TFA salt. ¹H NMR (DMSO-d₆) δ ppm8.18 (1H, s), 7.88-7.96 (3H, m), 7.77-7.82 (1H, m), 7.72-7.77 (1H, m),7.49 (1H, d, J=7.8 Hz), 7.27-7.38 (3H, m), 5.82 (2H, d, J=18.4 Hz), 2.54(3H, s); Mass Spectrum (ESI) m/e=468.1 (M+1); HPLC: a peak at 6.522 min.¹H NMR (DMSO-d₆) δ ppm 8.15 (1H, s), 7.91-7.96 (1H, m), 7.89 (2H, s),7.78-7.84 (1H, m), 7.74-7.78 (1H, m), 7.40-7.49 (1H, m), 7.18-7.34 (3H,m), 5.82 (2H, d, J=27.4 Hz), 2.66 (3H, s); Mass Spectrum (ESI) m/e=468.1(M+1); HPLC: a peak at 6.700 min.

Example 197-((2-(2-Chlorophenyl)-8-methylquinolin-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (280 mg, 1.1 eq) inDMF (3 mL) was treated with NaH (1.2 eq, 80 mg, 60%) and the reactionmixture was stirred at rt for 30 min before addition of3-(chloromethyl)-2-(2-chlorophenyl)-8-methylquinoline (500 mg, 1.7 mmol)in DMF (2 mL). After 2 h at rt, the mixture was partitioned betweenEtOAc (50 mL) and H₂O (30 mL), the layers were separated, and theaqueous layer was extracted with EtOAc (2×30 mL). The combined organiclayers were dried (Na₂SO₄), concentrated and purified by flashchromatography (0% to 25% EtOAc/hexane) to provide3-((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-2-(2-chlorophenyl)-8-methylquinolineas a white foam. This material (60 mg, 0.14 mmol) was dissolved in EtOH(4 mL) and treated with NH₃ gas for 3 min. The sealed tube was heated at80° C. for 4 days. The reaction mixture was concentrated and purified bycolumn chromatography on silica gel (eluent: DCM/MeOH, 20/1) to providea white solid [PI3Kδ IC₅₀=1968 nM]. ¹H-NMR (DMSO-d⁶) δ 7.94 (s, 1H),7.89 (s, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.37-7.62 (m, 6H), 6.96 (s, 2H),6.86 (d, J=3.6 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H), 5.30 (d, J=5.9 Hz, 2H),2.64 (s, 3H). Mass Spectrum (ESI) m/e=400 (M+1).

Example 205-Chloro-7-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

5-Chloro-7-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminewas prepared from 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine according tothe above procedure (example 44) as a white solid [PI3Kδ IC₅₀=20 nM].¹H-NMR (CDCl₃) δ 8.04 (s, 1H), 7.90 (s, 1H), 7.60 (d, J=8.3 Hz, 1H),7.54 (d, J=7.0 Hz, 1H), 7.15-7.43 (m, 6H), 5.23-5.45 (m, 4H), 2.69 (s,3H). Mass Spectrum (ESI) m/e=434 (M+1).

Example 21 Preparation of4-Amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one2-Amino-6-chloro-N-(2-methoxyphenyl)benzamide

SO₂Cl₂ (5.4 mL, 74 mmol, 2.5 eq) was added to a rapidly stirringsolution of 2-amino-6-chlorobenzoic acid (5 g, 29.14 mmol) in benzene(146 mL) and the mixture was stirred at reflux for 24 h. The mixture wasconcentrated under reduced pressure, and stripped down twice withbenzene to give brown oil. The resulting oil was dissolved in CHCl₃ (146mL) and to that solution was added o-anisidine and the mixture wasstirred at 65° C. for 2 h. The mixture was cooled to rt and theresulting precipitate was removed by filtration. The filtrate wasconcentrated under reduced pressure and purified by columnchromatography on a 120 g of Redi-Sep™ column using 0 to 100% gradientof EtOAc in hexane over 20 min as eluent to provide2-amino-6-chloro-N-(2-methoxyphenyl)benzamide as yellow solid. ¹H NMR(DMSO-d₆) δ ppm 9.44 (1H, s), 7.86 (1H, dd, J=7.9, 1.3 Hz), 7.13-7.21(1H, m), 7.04-7.11 (2H, m), 6.97 (1H, t, J=7.6 Hz), 6.66 (2H, dd,J=28.0, 7.9 Hz), 5.37 (2H, s), 3.81 (3H, s). Mass Spectrum (ESI)m/e=277.0 (M+1).

5-Chloro-2-(chloromethyl)-3-(2-methoxyphenyl)quinazolin-4(3H)-one

To a solution of 2-amino-6-chloro-N-(2-methoxyphenyl)benzamide (4.0813g, 14.75 mmol) in AcOH (39 mL) was added dropwise chloroacetyl chloride(3.6 mL, 45.2 mmol, 3 eq), and then the mixture was stirred at 110° C.for 3 h. The mixture was cooled to rt and concentrated under reducepressure. The residue was dissolved in H₂O and neutralized with K₂CO₃.The oily product was extracted with CH₂Cl₂ (3 times). The combinedorganic layers were dried with K₂CO₃, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography on a120 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexaneover 20 min as eluent to provide5-chloro-2-(chloromethyl)-3-(2-methoxyphenyl)quinazolin-4(3H)-one asoff-white solid. ¹H NMR (DMSO-d₆) δ ppm 7.83 (1H, t, J=7.9 Hz),7.69-7.74 (1H, m), 7.64 (1H, dd, J=7.9, 0.9 Hz), 7.51-7.58 (1H, m), 7.47(1H, dd, J=7.7, 1.6 Hz), 7.26 (1H, d, J=8.3 Hz), 7.09-7.17 (1H, m), 4.28(2H, dd, J=51.8, 12.5 Hz), 3.77 (3H, s). Mass Spectrum (ESI) m/e=335.0and 337.0 (M+1).

4-Amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one

To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.1 g, 0.616mmol), Cs₂CO₃ (0.3013 g, 0.925 mmol, 1.5 eq), and KI (0.0102 g, 0.0616mmol, 0.1 eq) in DMF (2 mL) was added5-chloro-2-(chloromethyl)-3-(2-methoxyphenyl)-quinazolin-4(3H)-one(0.2273 g, 0.678 mmol, 1.1 eq) and the mixture was stirred at 100° C.for 1 h. The mixture was concentrated under reduced pressure. The crudeproduct was purified by column chromatography on a 40 g of Redi-Sep™column using 0 to 100% gradient of:MeOH:NH₄OH (89:9:1) in CH₂Cl₂ over 14min as eluent to provide4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-oneas yellow solid (0.1707 g, 60%). The yellow solid was triturated withMeOH and filtered to provide4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one[PI3Kδ IC₅₀=13 nM] as yellow solid. ¹H NMR (DMSO-d₆) d ppm 9.53 (1H, d,J=4.7 Hz), 8.20 (1H, s), 8.14 (1H, d, J=4.7 Hz), 7.88 (1H, d, J=7.8 Hz),7.65-7.72 (1H, m), 7.49-7.59 (3H, m), 7.37 (1H, dd, J=8.2, 1.2 Hz), 7.31(1H, dd, J=8.6, 1.2 Hz), 7.15-7.21 (1H, m), 6.20 (1H, d, J=8.2 Hz),4.91-5.13 (2H, m), 3.85 (3H, s). Mass Spectrum (ESI) m/e=461.0 (M+1).

Example 22 Preparation of4-Amino-8-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one

To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.05 g, 0.308mmol), Cs₂CO₃ (0.1515 g, 0.46 mmol, 1.5 eq), and KI (0.0051 g, 0.0309mmol, 0.1 eq) in DMF (1 mL) was added8-chloro-3-(chloromethyl)-2-(2-chlorophenyl)quinoline (0.1 g, 0.309mmol, 1.0 eq) and the mixture was stirred at 140° C. for 1 h. Themixture was concentrated under reduced pressure. The crude product waspurified by column chromatography on a 40 g of Redi-Sep™ column using 0to 100% gradient of EtOAc in hexane over 14 min and then 100% isocraticof EtOAc for 14 min as eluent to provide4-amino-8-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one[PI3Kδ IC₅₀=33 nM] as white solid. ¹H NMR (DMSO-d₆) δ ppm 9.52 (1H, d,J=4.7 Hz), 8.25 (1H, s), 8.11 (1H, d, J=4.7 Hz), 8.09 (1H, s), 8.04 (1H,dd, J=8.4, 1.4 Hz), 7.97 (1H, dd, J=7.6, 1.4 Hz), 7.81 (1H, d, J=7.8Hz), 7.63 (1H, d, J=7.8 Hz), 7.57-7.61 (1H, m), 7.42-7.53 (3H, m), 6.14(1H, d, J=7.8 Hz), 5.40 (2H, s). Mass Spectrum (ESI) m/e=448.0 and 450.1(M+1).

Example 23

1,3,5-Trichlorotriazine (94 mg, 510 μmol) was added to dimethylformamide(0.04 mL, 510 μmol) at 25° C. After the formation of a white solid (10min), DCM (3 mL) was added, followed by1-(8-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethanol (140.0 mg, 464μmol), made from procedure K. After the addition, the mixture wasstirred at room temperature for 4 h. Water (10 mL) was added, and thendiluted with DCM (10 mL), the organic phase was washed with 15 mL of asaturated solution of NaHCO₃, followed by water and brine. The organiclayers were dried and concentrated. Purification of the residue by flashchromatography over silica gel, using 10% hexane in EtOAc, gave8-chloro-3-(1-chloroethyl)-2-(3-fluorophenyl)quinoline, Mass Spectrum(ESI) m/e=320.0 (M+1).

To a solution of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine¹ (28 mg,187 mmol) in DMF (2 mL) was added sodium hydride, 60% dispersion inmineral oil (15 mg, 375 μmol) at 0° C. and the mixture was stirred at rtfor 10 min. To the mixture was added a solution of8-chloro-3-(1-chloroethyl)-2-(3-fluorophenyl)-quinoline (60.0 mg, 187μmol) in DMF (1 mL) and the mixture was stirred at rt for 24 hrs. Themixture was poured into ice-water and extracted with Et₂O. The organiclayer was washed with brine, dried, and concentrated. The residue waspurified by flash chromatography over silica gel, using DCM and MeOH(95:5), then Chiral HPLC (Chiralpak IA column, 0.46×250 mm, 5 mm), using15% isopropanol in hexane as eluent, gave1-((S)-1-(8-chloro-2-(3-fluorophenyl)-quinolin-3-yl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,a fraction collected at 17 min, 99% ee at 254 nm, ¹H NMR (DMSO-d₆) δ ppm8.62 (1H, s), 8.09 (1H, d, J=8.2 Hz), 7.97 (1H, d, J=8.2 Hz), 7.96 (1H,s), 7.63 (1H, t, J=8.0 Hz), 7.35-7.41 (1H, m), 7.13-7.22 (3H, m),6.22-6.27 (1H, m), 2.47 (3H, s), 1.79 (3H, d, J=6.8 Hz). Mass Spectrum(ESI) m/e=433.1 (M+1).

Example 24

Using the same or analogous synthetic techniques and substituting withappropriate reagents as in Example 1, the following compound wasprepared:

1-((8-chloro-3-(4-fluorophenyl)quinoxalin-2-yl)methyl)-3-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-amine,¹H NMR (DMSO-d₆) δ ppm 8.08 (1H, dd, J=8.0, 1.2 Hz), 8.02 (1H, dd,J=8.0, 1.2 Hz), 8.01 (1H, s), 7.85 (1H, t, J=8.0 Hz), 7.58-7.64 (2H, m),7.11-7.18 (3H, m), 2.38 (3H, s). Mass Spectrum (ESI) m/e=420.1 (M+1).

Example 251-((5-Chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo-[3,4-c]pyrimidin-4-amine

Prepared according to Procedure I using5-chloro-3-(chloromethyl)-2-(2-chloro-phenyl)quinoline (0.700 g, 2.17mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.623 g, 2.39 mmol,1.1 eq) and NaH (0.078 g, 3.26 mmol, 1.5 eq) in DMF (15 mL).N-((8-chloro-2-(3-fluorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine[PI3Kδ IC₅₀=35 nM] was obtained after purification as a white solid.1H-NMR (MeOD) δ ppm 8.62 (s, 1H), 8.00 (s, 1H), 7.89-7.91 (m, 1H),7.82-7.85 (m, 1H), 7.43 (d, 1H, J=5.0 Hz), 7.29-7.32 (t, 1H), 7.18-7.22(t, 1H), 7.06 (d, 1H, J=5.0 Hz), 5.63 (s, 2H), Mass Spectrum (ESI)m/e=548 (M+1).

Example 261-((5-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Prepared according to Procedure J using1-((5-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.060 g, 0.110 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.032 g, 0.164 mmol, 1.5 eq), tetrakis(triphenylphosphine)palladium(0.006 g, 10 mol %), and sodium carbonate (2M aq. Sol., 6 eq) in DMF(0.2M)).1-((5-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminewas obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm8.56 (s, 1H), 8.01-8.05 (m, 3H), 7.87 (d, 1H, J=5.0), 7.80-7.83 (m, 1H),7.65 (s, 1H), 7.47 (d, 1H, J=5.0), 7.34 (t, 1H, J=5.0), 7.24 (t, 1H,J=5.0 Hz), 7.15 (d, 1H), 5.63 (s, 2H), 3.89 (s, 3H), Mass Spectrum (ESI)m/e=502 (M+1).

Example 27 Preparation of1-((8-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)-methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineas a TFA salt and1-((5-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineas a TFA salt1-((8-Chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((5-chloro-3-(2-chlorophenyl)-quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.7168 g,2.746 mmol) in 6 mL of DMF was added sodium hydride, 60% dispersion inmineral oil (0.2197 g, 5.492 mmol) at 0° C. and the mixture was stirredat room temperature. After 10 min, to the mixture was added a solutionof a mixture of 3-(bromomethyl)-5-chloro-2-(2-chlorophenyl)quinoxalineand 2-(bromomethyl)-5-chloro-3-(2-chlorophenyl)quinoxaline (1.061 g,2.883 mmol) in 6 mL of DMF and the mixture was stirred at roomtemperature. After 1 hr, the mixture was poured into ice-water (100 mL).The resulting precipitate was collected by filtration to give yellowsolid (1.2805 g). The yellow solid was purified by column chromatographyon a 40 g of Redi-Sep™ column using 0-100% gradient of EtOAc in hexaneover 14 min and then 100% isocratic of EtOAc for 16 min as eluent togive a mixture of two regioisomers as yellow solid. The yellow solid wassuspended in EtOAc and filtered to give1-((8-chloro-3-(2-chlorophenyl)-quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((5-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineas tan solid: LC-MS (ESI) m/z 547.9 [M+H]⁺.

1-((8-Chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineas a TFA salt and1-((5-Chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineas a TFA salt

A solution of a mixture of1-((8-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)-methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((5-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-aminein 3.2 mL of DMF was treated with 4-pyrazoleboronic acid pinacol ester(0.2124 g, 1.095 mmol), tetrakis(triphenylphosphine)palladium(0)(0.06324 g, 0.05473 mmol), and 2 M aq. sodium carbonate sol. (1.642 mL,3.284 mmol). The mixture was heated at 100° C. After 3.5 hr, the mixturewas removed from the heat and poured onto ice-water (100 mL). Theresulting precipitate was collected by suction filtration, washed withwater, and air-dried to give tan solid. The tan solid was purified bycolumn chromatography on a 40 g of Redi-Sep™ column using 0 to 100%gradient of CH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂ over 14 min and then100% isocratic of CH₂Cl₂:MeOH:NH₄OH (89:9:1) for 8 min as eluent to givea product mixture of two regioisomers as off-white solid. The off-whitesolid was dissolved purified by semi-prep-HPLC on C18 column using30-60% gradient of CH₃CN (0.1% of TFA) in water (0.1% of TFA) over 40min as eluent to give two separated regioisomers:1-((8-chloro-3-(2-chlorophenyl)-quinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineas a TFA salt as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.14 (1H,s), 8.12-8.13 (1H, m), 8.11 (1H, q, J=1.4 Hz), 7.85-7.94 (3H, m), 7.44(1H, d, J=7.8 Hz), 7.22-7.33 (3H, m), 5.89 (1H, s), 5.85 (1H, s); LC-MS:m/z 488.0 and 490.0 [M+1], (Exact Mass: 487.08) and1-((5-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineas a TFA salt as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.16 (1H,s), 8.12 (1H, s), 8.10 (1H, s), 7.87-7.95 (3H, m), 7.44-7.50 (1H, m),7.25-7.37 (3H, m), 5.87 (1H, s), 5.83 (1H, s); LC-MS: m/z 488.0 and490.0 [M+1], (Exact Mass: 487.08).

Example 28 Preparation of4-Amino-1-((3-(2-chlorophenyl)-8-methyl-quinoxalin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrileand4-Amino-1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

A suspension of a mixture of1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)-methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((3-(2-chloro-phenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine(Prepared in Example 15, 0.30000 g, 0.568 mmol) and copper(i) cyanide(0.305 g, 3.41 mmol) in 5 mL of pyridine was stirred at 100° C. After 8hr, the mixture was cooled to room temperature. The mixture wasconcentrated under reduced pressure. The crude mixture was purified bycolumn chromatography on a 40 g of Redi-Sep™ column using 0-100%gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAcfor 10 min as eluent to give a mixture of two regioisomers. The mixturewas purified (1.5 mL (˜50 mg)×4 injections) by semi-prep-HPLC on aGemini™ 10μ C18 column (250×21.2 mm, 10 μm) using 30-70% gradient ofCH₃CN (0.1% of TFA) in water (0.1% of TFA) over 40 min as eluent to givetwo fractions: each fraction was treated with saturated NaHCO₃ (50 mL)and extracted with CH₂Cl₂ (50 mL×1). The each organic layer was washedwith H₂O (30 mL×2), dried over Na₂SO₄, filtered, concentrated underreduced pressure to give two separated regioisomers:4-amino-1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrileas an off-white solid: ¹H NMR (500 MHz, DMF) δ ppm 8.16 (1H, s), 7.95(1H, d, J=8.1 Hz), 7.78-7.83 (1H, m), 7.73-7.78 (1H, m), 7.50-7.56 (1H,m), 7.39-7.45 (2H, m), 7.32-7.38 (1H, m), 5.86 (2H, s), 2.50 (3H, s);LC-MS (ESI) m/z 427.0 [M+H]⁺ and4-amino-1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrileas a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.13 (1H, s), 7.91(1H, dd, J=8.2, 0.9 Hz), 7.79-7.84 (1H, m), 7.76-7.80 (1H, m), 7.46-7.51(1H, m), 7.33-7.40 (2H, m), 7.26-7.32 (1H, m), 5.87 (2H, s), 2.68 (3H,s); LC-MS (ESI) m/z 427.1 [M+H]⁺.

Example 29 Preparation of1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)-methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A solution of a mixture of1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)-methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((3-(2-chloro-phenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine(Prepared in Example 15, 0.3000 g, 0.5685 mmol) in 3.3 mL of DMF wastreated with 1-methylpyrazole-4-boronic acid pinacol ester (0.2366 g,1.137 mmol), tetrakis(triphenylphosphine)palladium(0) (0.06569 g,0.05685 mmol), and 2 M aq. sodium carbonate sol. (1.705 mL, 3.411 mmol).The mixture was stirred at 100° C. After 50 min, The mixture was cooledto room temperature. To the mixture was added water (50 mL) and theresulting precipitate was collected by filtration to give the productsas a brown solid. The brown solid was purified by column chromatographyon a 40 g of Redi-Sep™ column using 0 to 100% gradient ofCH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂ over 14 min and then 100% isocraticof CH₂Cl₂:MeOH:NH₄OH (89:9:1) for 10 min as eluent to give a mixture oftwo regioisomers as a dark brown solid. The dark brown solid waspurified (1.5 mL (˜53 mg)×5 injections) by semi-prep-HPLC on a Gemini™10 μC18 column (250×21.2 mm, 10 μm) using 20-60% gradient of CH₃CN (0.1%of TFA) in water (0.1% of TFA) over 40 min as eluent to give twofractions: each fraction was treated with saturated NaHCO₃ (50 mL) andextracted with CH₂Cl₂ (50 mL×2). The combined organic layers wererespectively washed with H₂O (30 mL×2), dried over Na₂SO₄, filtered,concentrated under reduced pressure to give two separated regioisomers:1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineas an -off-white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.04 (1H, s),7.99 (1H, s), 7.90-7.95 (1H, m), 7.76-7.81 (1H, m), 7.72-7.76 (1H, m),7.63 (1H, d, J=0.8 Hz), 7.45 (1H, dd, J=7.4, 0.8 Hz), 7.28-7.33 (1H, m),7.20-7.27 (2H, m), 6.83 (2H, br. s.), 5.62-5.93 (2H, m), 3.87 (3H, s),2.57 (3H, s); LC-MS (ESI) m/z 482.0 [M+H]⁺ and1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineas a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.01 (1H, s), 7.97(1H, s), 7.94 (1H, dd, J=8.4, 1.0 Hz), 7.78-7.84 (1H, m), 7.74-7.78 (1H,m), 7.61 (1H, d, J=0.8 Hz), 7.38-7.43 (1H, m), 7.22-7.28 (1H, m),7.14-7.22 (2H, m), 6.81 (2H, br. s.), 5.59-5.95 (2H, m), 3.86 (3H, s),2.66 (3H, s); LC-MS (ESI) m/z 482.0 [M+H]⁺.

Example 30 Preparation of1-((8-chloro-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.07385g, 0.4951 mmol) in 1 mL of DMF was added Sodium hydride, 60% dispersionin mineral oil (0.03960 g, 0.9902 mmol) at 0° C. and the mixture wasstirred at room temperature. After 10 min at room temperature, to themixture was added a solution of8-chloro-3-(chloromethyl)-2-(2-(trifluoromethyl)phenyl)quinolinehydrochloride (Prepared in Example 6, 0.1944 g, 0.4951 mmol) in 2 mL ofDMF and the mixture was stirred at room temperature. After 50 min, themixture was poured into ice-water (100 mL). The resulting precipitatewas collected by filtration to give a brown solid (0.2185 g). The aq.filtrate also contained the desired product. The aq. filtrate wasextracted with CH₂Cl₂ (50 mL×3). The combined organis layers were washedwith brine (50 mL×1), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to give a colorless syrup (0.0346 g). The brownsolid and the colorless syrup were combined and purified by columnchromatography on a 40 g of Redi-Sep™ column using 0-100% gradient ofEtOAc in hexane over 14 min, then 100% isocratic of EtOAc for 10 min,and then 0% to 100% gradient of CH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂over 14 min as eluent to give1-((8-chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amineas an off-white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.24 (1H, s),8.03 (1H, dd, J=8.3, 1.3 Hz), 7.97 (1H, dd, J=7.5, 1.3 Hz), 7.95 (1H,s), 7.79-7.85 (1H, m), 7.57-7.67 (3H, m), 7.32-7.37 (1H, m), 7.24 (2H,br. s.), 5.30-5.42 (2H, m), 2.46 (3H, s); LC-MS (ESI) m/z 469.1 [M+H]⁺.

Example 31 Preparation of1-((5-chloro-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine5-Chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde

A mixture of 2,5-dichloroquinoline-3-carbaldehyde (1.9948 g, 8.8243mmol), 2-(trifluoromethyl)phenylboronic acid (1.8436 g, 9.7067 mmol),tetrakis(triphenyl-phosphine)palladium (0.50985 g, 0.44121 mmol), andsodium carbonate an-hydrous (4.6763 g, 44.121 mmol) in 88 mL ofCH₃CN—H₂O (3:1) was stirred at 100° C. After 5 hr, the mixture wascooled to room temperature and partitioned between EtOAc (100 mL) andwater (100 mL). The organic layer was washed with brine (50 mL×2), driedover MgSO₄, filtered, and concentrated under reduced pressure to give ared syrup. The red syrup was purified by silica gel columnchromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient ofEtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 30 minas eluent to give5-chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde as alight-yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.01 (1H, s), 9.19(1H, d, J=1.0 Hz), 8.08-8.14 (1H, m), 7.97-8.03 (2H, m), 7.89-7.95 (1H,m), 7.73-7.84 (2H, m), 7.55-7.61 (1H, m); LC-MS (ESI) m/z 336.1 [M+H]⁺.

5-Chloro-3-(chloromethyl)-2-(2-(trifluoromethyl)phenyl)quinolinehydrochloride

To a solution of5-chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde (2.1673g, 6.456 mmol) in 32 mL of THF at 0° C. was added sodium borohydride(0.3664 g, 9.684 mmol) and the mixture was stirred at 0° C. After 1 hrat 0° C., the mixture was partitioned between EtOAc (100 mL) and H₂O(100 mL), and the organic layer was washed with brine (50 mL×3), driedover Na₂SO₄, filtered, and concentrated under reduced pressure to give(5-chloro-2-(2-(trifluoromethyl)-phenyl)quinolin-3-yl)methanol as ayellow syrup: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.68-8.73 (1H, m),7.96-8.02 (1H, m), 7.90-7.95 (1H, m), 7.83-7.87 (1H, m), 7.68-7.83 (3H,m), 7.50-7.58 (1H, m), 5.63 (1H, t, J=5.3 Hz), 4.36 (2H, br. s.); LC-MS(ESI) m/z 338.0 [M+H]⁺. The product was carried on crude withoutpurification for the next step.

A solution of(5-chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanol (2.180 g,6.455 mmol) in 22 mL of CHCl₃ was treated with thionyl chloride (2.348mL, 32.27 mmol) dropwise, and the reaction mixture was stirred at roomtemperature. After 1.5 hr, the mixture was concentrated under reducedpressure and co-evaporated three times with CH₂Cl₂ to give5-chloro-3-(chloromethyl)-2-(2-(trifluoromethyl)phenyl)quinolinehydrochloride as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.86(1H, d, J=0.6 Hz), 7.99-8.05 (1H, m), 7.94 (1H, dd, J=7.4, 1.0 Hz),7.88-7.92 (1H, m), 7.81-7.87 (2H, m), 7.74-7.81 (1H, m), 7.61-7.66 (1H,m), 4.77 (2H, d, J=79.0 Hz); LC-MS (ESI) m/z 356.0 and 358.0 [M+H]⁺(Exact Mass of neutral form: 355.014). The yellow solid was carried oncrude without purification for the next step.

1-((5-Chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.0956 g,0.641 mmol) in 1 mL of DMF was added sodium hydride, 60% dispersion inmineral oil (0.0513 g, 1.28 mmol) at 0° C. and the mixture was stirredat room temperature. After 5 min at room temperature, to the mixture wasadded a solution of5-chloro-3-(chloromethyl)-2-(2-(trifluoromethyl)phenyl)quinolinehydrochloride (0.2767 g, 0.705 mmol) in 3 mL of DMF and the mixture wasstirred at room temperature. After 1.5 hr, the mixture was poured intoice-water (100 mL). The resulting precipitate was collected byfiltration to give an off-white solid. The off white solid was purifiedby column chromatography on a 40 g of Redi-Sep™ column using 0-100%gradient of EtOAc in hexane over 14 min and then 0% to 100% gradient ofCH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂ over 14 min as eluent to give anoff-white solid. The off-white solid was suspended in CH₂Cl₂-hexane(1:1) and filtered to give1-((5-chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amineas a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.44 (1H, d, J=0.8Hz), 7.96-8.02 (1H, m), 7.94 (1H, s), 7.84-7.88 (1H, m), 7.75-7.83 (2H,m), 7.52-7.64 (2H, m), 7.05-7.49 (3H, m, J=6.7 Hz), 5.42 (2H, s), 2.45(3H, s); LC-MS (ESI) m/z 469.1 [M+H]⁺.

Example 32 Preparation of1-((3-(2-chlorophenyl)-8-fluoroquinoxalin-2-yl)-methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((3-(2-chlorophenyl)-5-fluoroquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine3-(Bromomethyl)-2-(2-chlorophenyl)-5-fluoroquinoxaline and2-(Bromo-methyl)-3-(2-chlorophenyl)-5-fluoroquinoxaline

To a solution of 3-bromo-1-(2-chlorophenyl)propane-1,2-dione (Preparedin Procedure L, 2.3832 g, 9.114 mmol) in 61 mL of EtOAc was added asolution of 3-fluorobenzene-1,2-diamine (1.150 g, 9.114 mmol) at roomtemperature and the resulting red mixture was stirred at roomtemperature. After 3 hr, the mixture was concentrated in vacuo to give amixture of two regioisomers as a black syrup. The black syrup waspurified by column chromatography on a 80 g of Redi-Sep™ column using 0to 50% gradient of EtOAc in hexane over 25 min and then 100% isocraticof EtOAc for 4 min as eluent to give a mixture of3-(bromomethyl)-2-(2-chlorophenyl)-5-fluoroquinoxaline and2-(bromomethyl)-3-(2-chlorophenyl)-5-fluoroquinoxaline as a red syrup:LC-MS (ESI) two peaks of m/z 351.0 [M+H (⁷⁹Br)]⁺ and 352.9 [M+H(⁸¹Br)]⁺. The red syrup was carried on crude without furtherpurification for the next step.

1-((3-(2-Chlorophenyl)-8-fluoroquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineand1-((3-(2-Chlorophenyl)-5-fluoro-quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.6330 g,2.425 mmol) 5 mL of DMF was added Sodium hydride, 60% dispersion inmineral oil (0.1940 g, 4.850 mmol) at 0° C. and the mixture was stirredat room temperature. After 10 min at room temperature, to the mixturewas added a solution of a mixture of3-(bromomethyl)-2-(2-chlorophenyl)-5-fluoroquinoxaline and2-(bromomethyl)-3-(2-chlorophenyl)-5-fluoroquinoxaline (0.9379 g, 2.668mmol) in 5 mL of DMF and the mixture was stirred at room temperature.After 50 min, the mixture was poured into ice-water (100 mL). Theresulting precipitate was collected by filtration to give a yellowsolid. The yellow solid was purified by silica gel column chromatographyon a 40 g of Redi-Sep™ column using 0-100% gradient of EtOAc in hexaneover 14 min and then 100% isocratic of EtOAc for 16 min as eluent togive a mixture of1-((3-(2-chlorophenyl)-8-fluoroquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineand 1-((3-(2-chlorophenyl)-5-fluoroquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine as atan solid. The tan solid was separated by supercritical fluidchromatography (SFC) to give two separated regioisomers:1-((3-(2-chlorophenyl)-8-fluoroquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineas a white solid: ¹H NMR (400 MHz, chloroform-d) δ ppm 8.18 (1H, s),7.92-7.98 (1H, m), 7.72-7.80 (1H, m), 7.46-7.55 (1H, m), 7.36 (1H, dd,J=8.0, 1.0 Hz), 7.19-7.24 (1H, m), 7.12-7.17 (1H, m), 7.05-7.10 (1H, m),5.75-6.14 (4H, m); LC-MS (ESI) m/z 532.0 [M+H]⁺ and1-((3-(2-chlorophenyl)-5-fluoroquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineas a white solid: ¹H NMR (400 MHz, chloroform-d) δ ppm 8.20 (1H, s),7.86-7.92 (1H, m), 7.70-7.78 (1H, m), 7.45-7.53 (1H, m), 7.37-7.42 (1H,m), 7.24-7.30 (1H, m), 7.16-7.23 (2H, m), 5.76-6.04 (4H, m); LC-MS (ESI)m/z 532.0 [M+H]⁺.

Biological Assays

Recombinant expression of PI3KsFull length p110 subunits of PI3k α, β and δ, N-terminally labeled withpolyHis tag, were coexpressed with p85 with Baculo virus expressionvectors in sf9 insect cells. P110/p85 heterodimers were purified bysequential Ni-NTA, Q-HP, Superdex-100 chromatography. Purified α, β andδ isozymes were stored at −20° C. in 20 mM Tris, pH 8, 0.2M NaCl, 50%glycerol, 5 mM DTT, 2 mM Na cholate. Truncated PI3Kγ, residues 114-1102,N-terminally labeled with polyHis tag, was expressed with Baculo virusin Hi5 insect cells. The γ isozyme was purified by sequential Ni-NTA,Superdex-200, Q-HP chromatography. The γ isozyme was stored frozen at−80° C. in NaH₂PO₄, pH 8, 0.2M NaCl, 1% ethylene glycol, 2 mMβ-mercaptoethanol.

Alpha Beta Delta gamma 50 mM Tris pH 8 pH 7.5 pH 7.5 pH 8 MgCl2 15 mM 10mM 10 mM 15 mM Na cholate 2 mM 1 mM 0.5 mM 2 mM DTT 2 mM 1 mM 1 mM 2 mMATP 1 uM 0.5 uM 0.5 uM 1 uM PIP2 none 2.5 uM 2.5 uM none time 1 hr 2 hr2 hr 1 hr [Enzyme] 15 nM 40 nM 15 nM 50 nM

In Vitro Enzyme Assays.

Assays were performed in 25 μL with the above final concentrations ofcomponents in white polyproplyene plates (Costar 3355). Phospatidylinositol phosphoacceptor, Ptdlns(4,5)P2 P4508, was from EchelonBiosciences. The ATPase activity of the alpha and gamma isozymes was notgreatly stimulated by Ptdlns(4,5)P2 under these conditions and wastherefore omitted from the assay of these isozymes. Test compounds weredissolved in dimethyl sulfoxide and diluted with three-fold serialdilutions. The compound in DMSO (1 μL) was added per test well, and theinhibition relative to reactions containing no compound, with andwithout enzyme was determined. After assay incubation at roomtemperature, the reaction was stopped and residual ATP determined byaddition of an equal volume of a commercial ATP bioluminescence kit(Perkin Elmer EasyLite) according to the manufacturer's instructions,and detected using a AnalystGT luminometer.

Human B Cells Proliferation Stimulate by Anti-IgM Isolate Human B Cells:

Isolate PBMCs from Leukopac or from human fresh blood. Isolate human Bcells by using Miltenyi protocol and B cell isolation kit II.-human Bcells were Purified by using AutoMacs.column.

Activation of Human B Cells

Use 96 well Flat bottom plate, plate 50000/well purified B cells in Bcell proliferation medium (DMEM+5% FCS, 10 mM Hepes, 50 μM2-mercaptoethanol); 150 μL medium contain 250 ng/mL CD40L-LZ recombinantprotein (Amgen) and 2 μg/mL anti-Human IgM antibody (JacksonImmunoReseach Lab.#109-006-129), mixed with 50 μL B cell mediumcontaining PI3K inhibitors and incubate 72 h at 37° C. incubator. After72 h, pulse labeling B cells with 0.5-1 uCi/well ³H thymidine forovernight ˜18 h, and harvest cell using TOM harvester.

Compound IC501-((8-chloro-2-(2-fluorophenyl)-3-quinolinyl)methyl)-3-(1H- 0.018171pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine4-amino-1-((3-(2-chlorophenyl)-8-methyl-2- 0.083816quinoxalinyl)methyl)-1H-pyrazolo[3,4-d]pyrimidine- 3-carbonitrile4-amino-1-((3-(2-chlorophenyl)-5-methyl-2- 0.001989quinoxalinyl)methyl)-1H-pyrazolo [3,4-d]pyrimidine- 3-carbonitrile1-((3-(2-chlorophenyl)-8-methyl-2-quinoxalinyl)methyl)-3-(1- 0.01979methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4- amine1-((3-(2-chlorophenyl)-5-methyl-2-quinoxalinyl)methyl)-3-(1- 0.037023methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4- amine1-((5-chloro-2-(2-chlorophenyl)-3-quinolinyl)methyl)-3- 0.093431iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine1-((8-chloro-2-(2-(trifluoromethyl)phenyl)-3- 0.044789quinolinyl)methyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin- 4-amine1-((5-chloro-2-(2-(trifluoromethyl)phenyl)-3- 0.135691quinolinyl)methyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin- 4-amine1-((3-(2-chlorophenyl)-8-fluoro-2-quinoxalinyl)methyl)- 0.8176163-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine1-((3-(2-chlorophenyl)-5-fluoro-2-quinoxalinyl)methyl)- 0.554433-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine1-((5-chloro-2-(2-chlorophenyl)-3-quinolinyl)methyl)-3-(1- 0.046745methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin- 4-amine1-((1S)-1-(8-chloro-2-(3-fluorophenyl)-3-quinolinyl)ethyl)-3- 0.00157methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine2-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1- 0.512429yl)methyl)-3-(3-fluorophenyl)-6-methyl-4H- pyrido[1,2-a]pyrimidin-4-one

Human B Cells Proliferation Stimulate by IL-4 Isolate Human B Cells:

Isolate human PBMCs from Leukopac or from human fresh blood. Isolatehuman B cells using Miltenyi protocol-B cell isolation kit. Human Bcells were Purified by AutoMacs.column.

Activation of Human B Cells

Use 96-well flat bottom plate, plate 50000/well purified B cells in Bcell proliferation medium (DMEM+5% FCS, 50 μM 2-mercaptoethanol, 10 mMHepes). The medium (150 μL) contain 250 ng/mL CD40L-LZ recombinantprotein (Amgen) and 10 ng/mL IL-4 (R&D system # 204-IL-025), mixed with50 150 μL B cell medium containing compounds and incubate 72 h at 37° C.incubator. After 72 h, pulse labeling B cells with 0.5-1 uCi/well 3Hthymidine for overnight ˜18 h, and harvest cell using TOM harvester.

Specific T Antigen (Tetanus Toxoid) Induced Human PBMC ProliferationAssays

Human PBMC are prepared from frozen stocks or they are purified fromfresh human blood using a Ficoll gradient. Use 96 well round-bottomplate and plate 2×10⁵ PBMC/well with culture medium (RPMI1640+10% FCS,50 uM 2-Mercaptoethanol, 10 mM Hepes). For IC₅₀ determinations, PI3Kinhibitors was tested from 10 μM to 0.001 μM, in half log increments andin triplicate. Tetanus toxoid, T cell specific antigen (University ofMassachusetts Lab) was added at 1 μg/mL and incubated 6 days at 37° C.incubator. Supernatants are collected after 6 days for IL2 ELISA assay,then cells are pulsed with ³H-thymidine for ˜18 h to measureproliferation.

GFP Assays for Detecting Inhibition of Class Ia and Class III PI3K

AKT1 (PKBa) is regulated by Class Ia PI3K activated by mitogenic factors(IGF-1, PDGF, insulin, thrombin, NGF, etc.). In response to mitogenicstimuli, AKT1 translocates from the cytosol to the plasma membraneForkhead (FKHRL1) is a substrate for AKT1. It is cytoplasmic whenphosphorylated by AKT (survival/growth). Inhibition of AKT(stasis/apoptosis)-forkhead translocation to the nucleusFYVE domains bind to PI(3)P. the majority is generated by constitutiveaction of PI3K Class III

AKT Membrane Ruffling Assay (CHO-IR-AKT1-EGFP Cells/GE Healthcare)

Wash cells with assay buffer. Treat with compounds in assay buffer 1 h.Add 10 ng/mL insulin. Fix after 10 min at room temp and image

Forkhead Translocation Assay (MDA MB468 Forkhead-DiversaGFP Cells)

Treat cells with compound in growth medium 1 h. Fix and image.

Class III PI(3)P Assay (U2OS EGFP-2XFYVE Cells/GE Healthcare)

Wash cells with assay buffer. Treat with compounds in assay buffer 1 h.Fix and image.

Control for all 3 Assays is 10 μM Wortmannin:

AKT is cytoplasmicForkhead is nuclearPI(3)P depleted from endosomes

Biomarker Assay: B-Cell Receptor Stimulation of CD69 or B7.2 (CD86)Expression

Heparinized human whole blood was stimulated with 10 μg/mL anti-IgD(Southern Biotech, #9030-01). 90 μL of the stimulated blood was thenaliquoted per well of a 96-well plate and treated with 10 μL of variousconcentrations of blocking compound (from 10-0.0003 μM) diluted inIMDM+10% FBS (Gibco). Samples were incubated together for 4 h (for CD69expression) to 6 h (for B7.2 expression) at 37° C. Treated blood (50 μL)was transferred to a 96-well, deep well plate (Nunc) for antibodystaining with 10 μL each of CD45-PerCP (BD Biosciences, #347464),CD19-FITC (BD Biosciences, #340719), and CD69-PE (BD Biosciences,#341652). The second 50 μL of the treated blood was transferred to asecond 96-well, deep well plate for antibody staining with 10 μL each ofCD19-FITC (BD Biosciences, #340719) and CD86-PeCy5 (BD Biosciences,#555666). All stains were performed for 15-30 minutes in the dark atroom temperature. The blood was then lysed and fixed using 450 μL ofFACS lysing solution (BD Biosciences, #349202) for 15 minutes at roomtemperature. Samples were then washed 2× in PBS+2% FBS before FACSanalysis. Samples were gated on either CD45/CD19 double positive cellsfor CD69 staining, or CD19 positive cells for CD86 staining

Gamma Counterscreen: Stimulation of Human Monocytes for Phospho-AKTExpression

A human monocyte cell line, THP-1, was maintained in RPMI+10% FBS(Gibco). One day before stimulation, cells were counted using trypanblue exclusion on a hemocytometer and suspended at a concentration of1×10⁶ cells per mL of media. 100 μL of cells plus media (1×10⁵ cells)was then aliquoted per well of 4-96-well, deep well dishes (Nunc) totest eight different compounds. Cells were rested overnight beforetreatment with various concentrations (from 10-0.0003 μM) of blockingcompound. The compound diluted in media (12 μL) was added to the cellsfor 10 minutes at 37° C. Human MCP-1 (12 μL, R&D Diagnostics, #279-MC)was diluted in media and added to each well at a final concentration of50 ng/mL. Stimulation lasted for 2 minutes at room temperature.Pre-warmed FACS Phosflow Lyse/Fix buffer (1 mL of 37° C.) (BDBiosciences, #558049) was added to each well. Plates were then incubatedat 37° C. for an additional 10-15 minutes. Plates were spun at 1500 rpmfor 10 minutes, supernatant was aspirated off, and 1 mL of ice cold 90%MeOH was added to each well with vigorous shaking Plates were thenincubated either overnight at −70° C. or on ice for 30 minutes beforeantibody staining Plates were spun and washed 2× in PBS+2% FBS (Gibco).Wash was aspirated and cells were suspended in remaining buffer. RabbitpAKT (50 μL, Cell Signaling, #4058L) at 1:100, was added to each samplefor 1 h at rt with shaking Cells were washed and spun at 1500 rpm for 10minutes. Supernatant was aspirated and cells were suspended in remainingbuffer. Secondary antibody, goat anti-rabbit Alexa 647 (50 μL,Invitrogen, #A21245) at 1:500, was added for 30 minutes at rt withshaking Cells were then washed 1× in buffer and suspended in 150 μL ofbuffer for FACS analysis. Cells need to be dispersed very well bypipetting before running on flow cytometer. Cells were run on an LSR II(Becton Dickinson) and gated on forward and side scatter to determineexpression levels of pAKT in the monocyte population.

Gamma Counterscreen: Stimulation of Monocytes for Phospho-AKT Expressionin Mouse Bone Marrow

Mouse femurs were dissected from five female BALB/c mice (Charles RiverLabs.) and collected into RPMI+10% FBS media (Gibco). Mouse bone marrowwas removed by cutting the ends of the femur and by flushing with 1 mLof media using a 25 gauge needle. Bone marrow was then dispersed inmedia using a 21 gauge needle. Media volume was increased to 20 mL andcells were counted using trypan blue exclusion on a hemocytometer. Thecell suspension was then increased to 7.5×10⁶ cells per 1 mL of mediaand 100 μL (7.5×10⁵ cells) was aliquoted per well into 4-96-well, deepwell dishes (Nunc) to test eight different compounds. Cells were restedat 37° C. for 2 h before treatment with various concentrations (from10-0.0003 μM) of blocking compound. Compound diluted in media (12 μL)was added to bone marrow cells for 10 minutes at 37° C. Mouse MCP-1 (12μL, R&D Diagnostics, #479-JE) was diluted in media and added to eachwell at a final concentration of 50 ng/mL. Stimulation lasted for 2minutes at room temperature. 1 mL of 37° C. pre-warmed FACS PhosflowLyse/Fix buffer (BD Biosciences, #558049) was added to each well. Plateswere then incubated at 37° C. for an additional 10-15 minutes. Plateswere spun at 1500 rpm for 10 minutes. Supernatant was aspirated off and1 mL of ice cold 90% MeOH was added to each well with vigorous shakingPlates were then incubated either overnight at −70° C. or on ice for 30minutes before antibody staining Plates were spun and washed 2× inPBS+2% FBS (Gibco). Wash was aspirated and cells were suspended inremaining buffer. Fc block (2 μL, BD Pharmingen, #553140) was then addedper well for 10 minutes at room temperature. After block, 50 μL ofprimary antibodies diluted in buffer; CD11b-Alexa488 (BD Biosciences,#557672) at 1:50, CD64-PE (BD Biosciences, #558455) at 1:50, and rabbitpAKT (Cell Signaling, #4058L) at 1:100, were added to each sample for 1h at RT with shaking. Wash buffer was added to cells and spun at 1500rpm for 10 minutes. Supernatant was aspirated and cells were suspendedin remaining buffer. Secondary antibody; goat anti-rabbit Alexa 647 (50μL, Invitrogen, #A21245) at 1:500, was added for 30 minutes at rt withshaking Cells were then washed 1× in buffer and suspended in 100 μL ofbuffer for FACS analysis. Cells were run on an LSR II (Becton Dickinson)and gated on CD11b/CD64 double positive cells to determine expressionlevels of pAKT in the monocyte population.pAKT in vivo AssayVehicle and compounds are administered p.o. (0.2 mL) by gavage (OralGavage Needles Popper & Sons, New Hyde Park, N.Y.) to mice (TransgenicLine 3751, female, 10-12 wks Amgen Inc, Thousand Oaks, Calif.) 15 minprior to the injection i.v (0.2 mLs) of anti-IgM FITC (50 ug/mouse)(Jackson Immuno Research, West Grove, Pa.). After 45 min the mice aresacrificed within a CO₂ chamber. Blood is drawn via cardiac puncture(0.3 mL) (1 cc 25 g Syringes, Sherwood, St. Louis, Mo.) and transferredinto a 15 mL conical vial (Nalge/Nunc International, Denmark). Blood isimmediately fixed with 6.0 mL of BD Phosflow Lyse/Fix Buffer (BDBioscience, San Jose, Calif.), inverted 3X's and placed in 37° C. waterbath. Half of the spleen is removed and transferred to an eppendorf tubecontaining 0.5 mL of PBS (Invitrogen Corp, Grand Island, N.Y.). Thespleen is crushed using a tissue grinder (Pellet Pestle, Kimble/Kontes,Vineland, N.J.) and immediately fixed with 6.0 mL of BD PhosflowLyse/Fix buffer, inverted 3X's and placed in 37° C. water bath. Oncetissues have been collected the mouse is cervically-dislocated andcarcass to disposed. After 15 min, the 15 mL conical vials are removedfrom the 37° C. water bath and placed on ice until tissues are furtherprocessed. Crushed spleens are filtered through a 70 μm cell strainer(BD Bioscience, Bedford, Mass.) into another 15 mL conical vial andwashed with 9 mL of PBS. Splenocytes and blood are spun @ 2,000 rpms for10 min (cold) and buffer is aspirated. Cells are resuspended in 2.0 mLof cold (−20° C.) 90% methyl alcohol (Mallinckrodt Chemicals,Phillipsburg, N.J.). Methanol is slowly added while conical vial israpidly vortexed. Tissues are then stored at −20° C. until cells can bestained for FACS analysis.

Multi-Dose TNP Immunization

Blood was collected by retro-orbital eye bleeds from 7-8 week old BALB/cfemale mice (Charles River Labs.) at day 0 before immunization. Bloodwas allowed to clot for 30 minutes and spun at 10,000 rpm in serummicrotainer tubes (Becton Dickinson) for 10 minutes. Sera werecollected, aliquoted in Matrix tubes (Matrix Tech. Corp.) and stored at−70° C. until ELISA was performed. Mice were given compound orallybefore immunization and at subsequent time periods based on the life ofthe molecule. Mice were then immunized with either 50 μg of TNP-LPS(Biosearch Tech., #T-5065), 50 μg of TNP-Ficoll (Biosearch Tech.,#F-1300), or 100 μg of TNP-KLH (Biosearch Tech., #T-5060) plus 1% alum(Brenntag, #3501) in PBS. TNP-KLH plus alum solution was prepared bygently inverting the mixture 3-5 times every 10 minutes for 1 hourbefore immunization. On day 5, post-last treatment, mice were CO₂sacrificed and cardiac punctured. Blood was allowed to clot for 30minutes and spun at 10,000 rpm in serum microtainer tubes for 10minutes. Sera were collected, aliquoted in Matrix tubes, and stored at−70° C. until further analysis was performed. TNP-specific IgG1, IgG2a,IgG3 and IgM levels in the sera were then measured via ELISA. TNP-BSA(Biosearch Tech., #T-5050) was used to capture the TNP-specificantibodies. TNP-BSA (10 μg/mL) was used to coat 384-well ELISA plates(Corning Costar) overnight. Plates were then washed and blocked for 1 husing 10% BSA ELISA Block solution (KPL). After blocking, ELISA plateswere washed and sera samples/standards were serially diluted and allowedto bind to the plates for 1 h. Plates were washed and Ig-HRP conjugatedsecondary antibodies (goat anti-mouse IgG1, Southern Biotech #1070-05,goat anti-mouse IgG2a, Southern Biotech #1080-05, goat anti-mouse IgM,Southern Biotech #1020-05, goat anti-mouse IgG3, Southern Biotech#1100-05) were diluted at 1:5000 and incubated on the plates for 1 h.TMB peroxidase solution (SureBlue Reserve TMB from KPL) was used tovisualize the antibodies. Plates were washed and samples were allowed todevelop in the TMB solution approximately 5-20 minutes depending on theIg analyzed. The reaction was stopped with 2M sulfuric acid and plateswere read at an OD of 450 nm.

For the treatment of PI3Kδ-mediated-diseases, such as rheumatoidarthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis,psoriasis, inflammatory diseases, and autoimmune diseases, the compoundsof the present invention may be administered orally, parentally, byinhalation spray, rectally, or topically in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers, adjuvants,and vehicles. The term parenteral as used herein includes, subcutaneous,intravenous, intramuscular, intrasternal, infusion techniques orintraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis,psoriatic arthritis, psoriasis, inflammatory diseases, and autoimmunediseases and the like.

The dosage regimen for treating PI3Kδ-mediated diseases, cancer, and/orhyperglycemia with the compounds of this invention and/or compositionsof this invention is based on a variety of factors, including the typeof disease, the age, weight, sex, medical condition of the patient, theseverity of the condition, the route of administration, and theparticular compound employed. Thus, the dosage regimen may vary widely,but can be determined routinely using standard methods. Dosage levels ofthe order from about 0.01 mg to 30 mg per kilogram of body weight perday, preferably from about 0.1 mg to 10 mg/kg, more preferably fromabout 0.25 mg to 1 mg/kg are useful for all methods of use disclosedherein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

Likewise, the compounds of this invention may exist as isomers, that iscompounds of the same molecular formula but in which the atoms, relativeto one another, are arranged differently. In particular, the alkylenesubstituents of the compounds of this invention, are normally andpreferably arranged and inserted into the molecules as indicated in thedefinitions for each of these groups, being read from left to right.However, in certain cases, one skilled in the art will appreciate thatit is possible to prepare compounds of this invention in which thesesubstituents are reversed in orientation relative to the other atoms inthe molecule. That is, the substituent to be inserted may be the same asthat noted above except that it is inserted into the molecule in thereverse orientation. One skilled in the art will appreciate that theseisomeric forms of the compounds of this invention are to be construed asencompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention arepharmaceutically acceptable esters of a carboxylic acid or hydroxylcontaining group, including a metabolically labile ester or a prodrugform of a compound of this invention. A metabolically labile ester isone which may produce, for example, an increase in blood levels andprolong the efficacy of the corresponding non-esterified form of thecompound. A prodrug form is one which is not in an active form of themolecule as administered but which becomes therapeutically active aftersome in vivo activity or biotransformation, such as metabolism, forexample, enzymatic or hydrolytic cleavage. For a general discussion ofprodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use. Esters of acompound of this invention, may include, for example, the methyl, ethyl,propyl, and butyl esters, as well as other suitable esters formedbetween an acidic moiety and a hydroxyl containing moiety. Metabolicallylabile esters, may include, for example, methoxymethyl, ethoxymethyl,iso-propoxymethyl, α-methoxyethyl, groups such asα-((C₁-C₄)-alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethylgroups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C₁-C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl, etc.; acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; orα-acyloxy-α-substituted methyl groups, for example α-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solidswhich can be crystallized from common solvents such as ethanol,N,N-dimethyl-formamide, water, or the like. Thus, crystalline forms ofthe compounds of the invention may exist as polymorphs, solvates and/orhydrates of the parent compounds or their pharmaceutically acceptablesalts. All of such forms likewise are to be construed as falling withinthe scope of the invention.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound having the structure:

or any pharmaceutically-acceptable salt thereof, wherein: X¹ is C(R⁹) orN; X² is N; Z is —CR¹¹═CR¹¹—; n is 0, 1, 2 or 3; R¹ is a direct-bondedor oxygen-linked saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms selectedfrom N, O and S, but containing no more than one O or S, wherein theavailable carbon atoms of the ring are substituted by 0, 1 or 2 oxo orthioxo groups, wherein the ring is substituted by 0 or 1 R²substituents, and the ring is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄-alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl; R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² isselected from C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,—(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle,—O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)hetero cycle,—NR^(a)(C₁₋₃alkyl)hetero aryl, —NR^(a)(C₁₋₃alkyl)hetero cycle,—(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl allof which are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl; R³ is selectedfrom H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl; R⁴ is, independently, in each instance, halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄halo alkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl or C₁₋₄haloalkyl; R⁵ is, independently, in eachinstance, H, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by1, 2 or 3 substituents selected from halo, cyano, OH, OC₁₋₄alkyl,C₁₋₄alkyl, C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groups together form a C₃₋₆spiroalkylsubstituted by 0, 1, 2 or 3 substituents selected from halo, cyano, OH,OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃halo alkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl; R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F,I, OR^(a), NR^(a)R^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl; R⁷is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl; R⁸ is selected from H,C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl; R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano,nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); R¹⁰ is H,C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a), C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a); R¹¹ is selected from H, halo,C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ isC₁₋₉alkyl or C₁₋₄alkyl(phenyl) wherein either is substituted by 0, 1, 2,3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I; or R¹¹ is a saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1,2, 3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); R^(a) isindependently, at each instance, H or R^(b); and R^(b) is independently,at each instance, phenyl, benzyl or C₁₋₆alkyl, the phenyl, benzyl andC₁₋₆alkyl being substituted by 0, 1, 2 or 3 substituents selected fromhalo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,—N(C₁₋₄alkyl)C₁₋₄alkyl.
 2. A compound according to claim 1, having thestructure:


3. A compound according to claim 1, having the structure:


4. A compound according to claim 1, having the structure:


5. A compound according to claim 1, wherein R³ is F, Cl or Br; and n isO.
 6. A compound according to claim 1, wherein R¹ is phenyl substitutedby 0 or 1 R² substituents, and the phenyl is additionally substituted by0, 1, 2 or 3 substituents independently selected from halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄halo alkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄halo alkyl.
 7. A compound according toclaim 1, wherein R¹ is a direct-bonded or oxygen-linked saturated,partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic ringcontaining 1, 2, 3 or 4 atoms selected from N, O and S, but containingno more than one O or S, wherein the available carbon atoms of the ringare substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 0 or 1 R² substituents, and the ring is additionallysubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, nitro, cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.
 8. A method of treatingrheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriaticarthritis, psoriasis, inflammatory diseases and autoimmune diseases,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, skin complaints with inflammatorycomponents, chronic inflammatory conditions, autoimmune diseases,systemic lupus erythematosis (SLE), myestenia gravis, rheumatoidarthritis, acute disseminated encephalomyelitis, idiopathicthrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome andautoimmune hemolytic anemia, allergic conditions and hypersensitivity,comprising the step of administering a compound according to claim
 1. 9.A method of treating cancers, which are mediated, dependent on orassociated with p110δ activity, comprising the step of administering acompound according to claim
 1. 10. A pharmaceutical compositioncomprising a compound according to claim 1 and apharmaceutically-acceptable diluent or carrier.